The first act of Millennium Approaches sets up all the major storylines of this overlapping plot. Roy Cohn, a lawyer and powerbroker, offers his young protégé, Joe Pitt, a chance to work for the Justice department in Washington, DC. Joe is excited to go join the conservative Reagan revolution. But first he's got to convince his wife, Harper, who we soon learn spends most of her time hallucinating on the prescription drug valium. As the two argue over going to Washington, Harper's suspicions that Joe is secretly gay come to light, though he denies it.
Meanwhile, we also meet Louis Ironson and Prior Walter, the other main couple in the play. When Prior reveals to Louis the first of many lesions to come, the reality of AIDS crashes down on the two men. Prior seems worried that Louis will desert him, and so does Louis. Prior gets sicker and begins to hear a mystical voice. Joe and Louis have a run-in in a bathroom. Louis assumes Joe is gay, but Joe again denies it.
The first act ends with Roy Cohn in his doctor's office. Is comes out that Roy is gay and that he has AIDS.
The second act begins with an incredibly sick Prior crumpled and bleeding on the floor. Both he and Louis freak out, and Prior is rushed to the hospital. At the same time, tensions continue to mount between Joe and Harper about the possible move to Washington and whether or not Joe is gay. Joe goes to Roy Cohn for advice, and Roy pressures him to take the job no matter what the personal cost might be.
Meanwhile, Louis drifts further and further from Prior, having sex with an anonymous man in the park and moving out of his and Prior's apartment while Prior is still in the hospital. Having not seen Louis for several days, Prior takes comfort in a visit from his best friend and ex-lover, Belize. Prior continues to hear the mysterious voice and worries that he's going insane.
Joe has another meeting with Roy, and it comes out that the real reason Roy wants Joe to come to the Justice Department is to help keep Roy from getting disbarred: his life of corruption is finally catching up to him. Joe is deeply conflicted about this, and he seems to take comfort in a conversation with Louis about the nature of justice. The bond between the two men is growing.
Joe finally takes the plunge, calling his conservative Mormon mother, Hannah, and admitting to her that he's gay. She can't deal with it and tells him to go home to his wife. The second act comes to a head with Joe admitting to Harper that he's gay and Louis telling Prior that he's moved out. Needless to say, neither Harper nor Prior is pleased, and explosively emotional scenes ensue. Harper runs out on Joe, and Louis leaves Prior alone in his hospital room. The act closes in Salt Lake City, where Hannah prepares to sell her house so she can move to New York City.
The final act begins with Prior talking to the ghosts of two of his ancestors, who tell him that a great messenger is coming to him. Meanwhile, Louis has coffee and talks politics with Belize, and we see just how guilt-ridden Louis is for abandoning Prior. As he's being released from the hospital, Prior has an intense vision of a flaming book.
The last we see of Harper in this part of the play. She is hanging out in her own hallucinated version of Antarctica. Hannah has made it to NYC, though she's lost somewhere in the Bronx. Joe goes to Roy and finally refuses to take the job in Washington, saying that Harper is missing and that he just can't do the unethical things Roy wants him to do. The two men almost get in a fight, and when Joe leaves, the very sick Roy collapses to the ground. The ghost of Ethel Rosenberg appears. She's a famous alleged Soviet spy whom Roy broke the law to see executed. She dials 911 for Roy.
In the play's final scenes, the ghosts of Prior's ancestors appear again, announcing that the moment has arrived; the messenger will make her appearance. Before this happens, Louis materializes in Prior's dream and the two share a dance. Louis disappears, and Prior is left dancing alone. Meanwhile, back in reality, Louis and Joe meet in the park. Joe comes on to Louis and the two go back to Louis' place together. In Prior's bedroom things are going crazy. There's an insane noise, wild lights, and the walls start to shake. In the climactic moment of Millennium Approaches, an angel crashes through Prior's ceiling, announcing that Prior is a prophet and that the "Great Work begins" (3.7.47).