Millennium Approaches opens with Rabbi Isador Chemelwitz next to a coffin with the body of Sarah Ironson inside. Sarah was a member of an influential Jewish family who came to America hoping to build a better life for her family. The Rabbi sadly notes how soon there will no longer be people like Sarah because the world is changing.
The scene shifts to Joe Pitt, who is waiting in Roy Cohn’s office. Roy is talking on the phone, swearing from time to time; Joe advises him to not take the Lord’s name in vain, revealing that he is a Mormon. Roy offers Joe a job in the Justice Department, but Joe tells him that he would like to talk with his wife first.
Meanwhile, Joe’s wife, Harper, is sitting alone in her apartment talking to Mr. Lies, a hallucination of hers. When Joe arrives, the hallucination disappears and Joe asks Harper if she would like to move to Washington. Harper tries to convince him to not take the job, saying she has things to do here in Brooklyn. Joe knows something is wrong with Harper, and he asks her how many pills of Valium she had taken in that day. Harper admits that she had taken a few, so Joe tries to calm her down and convince her that things will become better between them.
Meanwhile, Sarah’s grandson, Louis Ironson, and his lover, Prior Walter, sit outside the funeral home. Prior tells Louis that he has AIDS and Louis starts to panic. Louis leaves but promises to return. Later, Louis asks Rabbi Chemelwitz what the Bible says about abandoning a loved one in a time of need, but the Rabbi has no answer to this question.
A week later, Joe and Louis meet in the courthouse where they both work. Louis is crying, so Joe tries to comfort him. Louis complains about the lawyers who saw him crying; during the conversation with Joe, he makes a reference towards gay people. Joe replies that he isn’t gay and Louis, skeptical, leaves the bathroom after he kisses Joe on the cheek.
Prior has a dream in which he dresses in drag to try to cheer himself up when a woman appears. Harper is also having a dream and is surprised to see Prior in her hallucination. Prior tries to convince her that she is actually in his dream when Harper notices how sick Prior looks. She claims she can see deep into him, and Prior realizes he can do the same. He then tells Harper that her husband is gay; while she tries to deny this, she subconsciously admits it. After Harper disappears, Prior hears a strange voice calling him and feathers start to fall from the sky.
The next scene moves to the two couples placed at opposite sides of the stage: Harper and Joe on one side and Louis and Prior on the other side. Louis and Prior discuss the progress of Prior’s AIDS, which is getting worse, and Louis asks Prior if he would hate him if walked out in him. Prior responds by telling Louis that he would hate him forever for abandoning him.
Roy is visiting his doctor, Henry, who tells him that he has symptoms of AIDS. The doctor avoids using the word "gay," knowing that it will anger Roy. Roy tells the doctor that labels like "gay" and "AIDS" mean that a man has no real power: he insists that his disease be deemed liver cancer. Henry urges Roy to use his influence to be included in a trial for a new AIDS drug.
The second act, In Vitro, opens with Prior and Louis in their apartment in the middle of the night. Suddenly, Prior wakes up in pain and cries for Louis to wake up. When Prior refuses to go to the hospital, Louis calls for an ambulance.
Joe comes home to find Harper in a distressed state. Harper asks him vehemently where he was, tells Joe that she is going to have a baby (which is a lie), and urges Joe to leave for Washington without her.
Meanwhile, Louis talks with one of Prior’s nurses, who tries to cheer him up. Saddened by his boyfriend’s condition, Louis decides to take a walk in the park to clear his head. Louis ends up in Central Park’s Ramble, a region known for being a place where men meet up to have sex.
There, Louis meets a man and asks him to punish him. The two start having sexual intercourse. Even though the condom breaks, Louis urges the man to continue, telling him that he doesn’t care if he gets infected or not. The man is perturbed and leaves.
After the discussion with Harper, Joe goes to a bar where he meets Roy. Joe tells Roy about Harper’s addiction and Roy urges him to accept the job offer in Washington, assuring him that he will mentor him. Roy also tells Joe that he is dying of cancer, hiding the fact that he has AIDS.
In his hospital room, Prior wakes up alone. He is visited by Belize, a drag queen, nurse, and former lover. Prior tells Belize that he has been hearing voices but asks Belize not to tell anyone about it. After Belize leaves, Prior starts to hear the voices again telling him that he must prepare to perform a great work.
Joe, Roy, and Martin Heller, a friend of Roy’s at Justice, are at a restaurant eating dinner. Both Roy and Martin try to persuade Joe to accept the job offer, telling him that from that position, Joe will be able to help them by disbarring one of Roy’s political opponents. Joe refuses to do something unethical; Roy starts to yell at him but is unable to convince him.
In the next scene, Joe and Louis meet in front of the courthouse where they both work. Joe tells Louis about his fears and his desire for freedom. There is sexual tension between the two of them, though Louis dislikes that Joe is a Republican.
Later that night, Joe returns home drunk and he calls his mother Hannah from a pay phone. Joe tells her that he is homosexual but his mother ignores this, telling Joe that drinking is a sin and that he should go home.
When Joe arrives home he has an argument with Harper. Joe tells her that he still loves her and that he will never abandon her, but he also confesses that he knew something was different with him even before he married her. Harper insists that he go to Washington and leave her alone. Harper realizes that the man who terrifies her during the times when she is hallucinating is her husband, so she calls for Mr. Lies and they both disappear.
Meanwhile, Prior and Louis have an argument in Prior’s hospital room. The argument ends when Prior tells Louis to leave after Louis tells him that he wants to move out but will still visit him from time to time.
In Salt Lake City, Hannah Pitt, Joe’s mother, talks with her friend and real estate agent, Sister Ella, about selling her house and moving to New York because she wants to be there for her son. Ella is skeptical about New York and warns Hannah to be careful.
The third act’s first scene takes place in Prior’s hospital room. He is awakened by a man who claims to be one of his ancestors. The ghost tells Prior that he lived during the 13th century in England, was a squire, and died of the Black Death. Another ancestor appears; the second ghost claims that he died during the plague in the 17th century. Both ghosts claim that they have been sent to prepare the way for the unseen messenger. They start to chant in English and Hebrew.
The next scene opens with Louis and Belize talking about politics in a coffee shop. They start to argue about race and religion, but their conversation soon starts to turn to Prior. Louis asks Belize to tell Prior that he still loves him, but Belize tells him that he can’t help him anymore. Belize leaves just as it starts snowing.
Prior is talking with his nurse about the progression of his illness. Suddenly, Prior hears Emily talk in Hebrew and a book appears. Emily claims she cannot see the things described by Prior.
Newly arrived from Utah, Hannah is lost in the Bronx and is trying to get to Brooklyn. With some prodding, a homeless woman tells her how to get to the Mormon Visitors' Center in Manhattan.
Joe’s refusal to go to Washington makes Roy irate. Joe continues to claim that he will not do something that goes against his ethics, and he leaves after Roy tells him about his involvement in the execution of Ethel Rosenberg. As soon as Joe leaves, pain takes over Roy and he falls to the ground. The ghost of Ethel Rosenberg appears and helps Roy by calling an ambulance.
An Angel appears to Prior and calls him a prophet. The angel tells Prior that the great work will begin. At first, Prior is scared, but then he finds himself sexually aroused by the presence of the Angel.
During this time, Joe and Louis meet in a park, where they kiss. Louis asks Joe to go home with him and after a few moments, Joe agrees to go with him.
The second part of the play is entitled Perestroika and opens with Aleksii Antedilluvianovich Prelapsarianov, who talks to a crowd and asks them a series of rhetorical questions about the meaningless of life today. The scene then moves to a frightened Prior, lying on the floor before the Angel, whom he tells to go away.
In Louis’s apartment, Joe tries to resist Louis’s sexual proposals, but he gives in to his desires.
Meanwhile, Harper is hallucinating that she is in Antarctica with Mr. Lies and that she has a pine tree. A spectral version of Joe enters and tells her that he is going on an adventure but that she can’t come. After he disappears, Harper realizes that she is dirty and disheveled in New York and that she tore down the tree from an arboretum. The scene ends when a police car pulls over and Harper surrenders. The police call Joe’s apartment and Hannah picks up. She plans to go to the police station to get Harper.
Belize talks with Prior on the phone while working in the hospital. Prior tells Belize about his dream and asks him to go to his house; however, before Belize leaves the hospital, Roy’s doctor Henry gives him Roy’s chart and he finds that Roy has AIDS. Belize goes to take care of Roy, but Roy is racist and rude to him. In response, Belize threatens him, and Roy grudgingly admires his attitude. Roy asks him to stay; moved by Roy’s condition, Belize tells him not to accept any experimental drugs or radiation as they will only make him feel worse. He should also not agree to placebos in place of the drugs. Before Belize can exit the room, Roy asks him if he will die soon, and Belize confirms his fears.
Meanwhile, Hannah takes care of Harper while Louis and Joe start a relationship. During a day spent together, Joe tries to make Louis feel less guilty about him leaving Prior but is unsuccessful.
Book Two of Perestroika opens with the funeral of one of Belize and Prior’s friends. Prior is dressed strangely in ascetic black clothing and tells Belize that an Angel gave him a Book when she visited him. After he finds the Book, he and the Angel have sexual intercourse. The Angel tells him about who the Angels are and how God got tired of them and made humans instead. He abandoned the Angels and went to the humans. The Angels want to try and get God back, but they cannot do so unless humans stop moving, migrating, and progressing, which is what attracted God to them in the first place.
After hearing the Angel’s perspective, Prior rejects the prophecy. Before disappearing, the Angel tells him that he has nowhere to hide. After Belize hears the story, he tries to convince Prior that maybe the Angel was just a hallucination. Prior admits that the Angel may be a result of his illness, but at the same time he insists that she might be real.
Meanwhile, Roy is in the hospital growing worse and worse; he continues to have hallucinations about Ethel. Belize takes care of him and notices the stash of drugs Roy has. After persuading him, Roy gives Belize a bottle of AZT, an experimental AIDS drug.
Harper and Prior randomly meet up at the Mormon Visitors' Center. A diorama show begins with a Mormon family moving to Utah. Harper thinks the father is played by Joe and the mother by Harper. Then Louis appears and argues with Joe about his work ethic. Prior thinks that he is hallucinating, but Hannah tells him that Louis appears in the show every time she goes there. On stage, Louis and Joe continue to argue until the curtain falls. After the show, Hannah and Prior try to find the actors who played on stage, but they realize that they imagined everything. The mother in the scene comes to life and talks to Harper about the state of the world.
Louis and Joe sit on the beach together. Joe confesses his love for Louis, but Louis expresses his wish to see Prior again. Louis leaves and calls Prior, asking to see him. Roy and Belize are talking in Roy’s hospital room. Roy’s health is poor enough to the point where he is hallucinating about Heaven. Scared, Belize leaves Roy alone to his hallucinations. On another day in Roy’s hospital room, Joe visits him and tells Roy that he now lives with a man. Roy gets angry, telling him to never think about men again and to return to his wife; then, he pulls out his IV tube, splattering blood on the floor and smearing it on Joe, and orders him to leave. After Joe leaves, the ghost of Ethel appears once more.
Louis meets with Prior in the park. Louis wants to be with Prior again, but Prior refuses, telling him to come before him only when he will have visible proof of the pain he claims to feel.
Prior and Belize go to Joe’s work to spy on Joe because Prior is curious what the man who is sleeping with his boyfriend is like. Prior tells Joe that he looks just like the dummy in the show he saw at the Mormon Visitors' Center. Joe recognizes Belize and corners him, but he leaves them alone when Prior pretends to be a mental patient.
After the incident, Belize meets with Louis and tells him that he is concerned about Prior’s health and about the hallucinations he has. Louis tells Belize that he stopped seeing Joe, but Belize doesn’t believe him. Instead, Belize bitterly tells him that Joe is sleeping with the infamous Roy Cohn, which infuriates Louis because he sees Roy as pure evil. Belize has no time for Louis’s ignorance and claims that Louis is wrong and only loves ideals. Belize thinks America and Roy Cohn are one in the same: evil, corrupt, and terminally ill.
Joe visits his mother at the Mormon Visitors' Center, where he is also looking for the missing Harper. He and Hannah exchange heated words and he leaves. Prior arrives right after, hoping to talk to Joe to warn him about how Louis hates weakness, sickness, and aging. He and Hannah find common ground, but Prior collapses because of his illness. He asks Hannah to take him to the hospital.
Joe finds Harper barely dressed and wet from rain. Joe tells her that he wants to return to her despite seeing her current state.
Prior returns to the hospital with Hannah. Knowing that she is a religious person, Prior asks her whether any prophet refused to accept a mission received from an Angel. She does not think his questions about Angels are crazy: she says that, if a prophecy doesn’t work, then one should reject it.
Meanwhile, Joe keeps his promise and returns to Harper. Despite this, he doesn’t feel comfortable having sex with her, and Harper knows that he fantasizes about other men. Joe leaves, telling her that he needs to clear his head. She finally sees the truth: their marriage is over.
Joe goes to Louis’s apartment where Louis, disgusted by his assumption that Joe slept with the evil Roy, criticizes him for the way he handled some cases for the Judge he works for. Louis accuses Joe of sleeping with Roy, and Joe gets angry to the point where he starts beating Louis. Ashamed of what he has done, Joe leaves Louis’s apartment.
Roy is near death. Before he dies, he is visited by Ethel’s ghost, who tells him that he was disbarred. Roy pretends to hallucinate in order to evoke her sympathy, and thus tricks Ethel into singing him a song before dying.
The fifth act begins in Prior’s hospital room, in which the Angel appears once more. Hannah also sees the Angel and she tells Prior that he must wrestle with the Angel if he wants to reject the prophecy. He and the Angel commence wrestling, and despite the fact that she is stronger than him, he holds on and wearies her until she agrees. A ladder descends from Heaven and Prior, though frightened, starts to climb it. Before the Angel disappears, she blesses Hannah.
In Heaven, Prior sees Harper. He wonders if she is dead but she explains that she isn’t, and is returning to Earth. Harper disappears and the Angel reappears. She brings Prior before a Council composed of the seven Angels. They talk about the nuclear accident at Chernobyl, but their conversation is interrupted by Prior telling them he wants to give the Book back because it is human nature to move from one place to another, to progress, and to desire. Prior leaves, but not before asking to be blessed with more life. The Angels refuse, and Prior decides to return.
Prior wakes up in his hospital room with Hannah, Belize, and Emily the nurse, who tells him his fever has broken and it looks like he is one of the luckier ones. Belize gives Prior the AZT pills, but Prior isn’t sure if he wants to take them. Louis expresses his wish to go back to Prior, but Prior rejects him.
Meanwhile, Harper leaves Joe one more time, stating that she will never return to him again. She begins a new life and takes a flight somewhere far away. On the plane, she hallucinates and sees the ozone layer again, but this time the layer is whole again.
The play ends with an epilogue five years after the close of Act Five. Prior, Louis, Belize, and Hannah are sitting on the rim of the Bethesda Fountain on a crisp winter’s day, discussing recent events such as the fall of the Berlin Wall. Prior speaks directly to the audience, telling them that he will continue to struggle to live and that he hopes he will be able to see the new Millennium.
