Millennium Approaches (Episodes 1-3): It is 1985 and AIDS is causing mass death in USA. In Manhattan, Prior Walter tells Louis, his lover, that he has AIDS; Louis, unable to handle it, leaves him. Joe Pitt, a Mormon and Republican attorney, is pushed by right-wing fixer Roy Cohn toward a job at the US Department of Justice. Both Pitt and Cohn are in the closet: Pitt out of shame and religious turmoil, Cohn to preserve his power and image. Pitt's wife Harper is strung out on Valium, hallucinating constantly and longs to escape from her sexless marriage. An angel with ulterior motives commands Prior to become a prophet.

Perestroika (Episodes 4-6): Prior is helped in his decision by Joe's mother, Hannah, and Belize, a close friend and drag queen. Joe leaves his wife and goes to live with Louis, but it does not work out because of ideological differences. Roy is diagnosed with AIDS and dying, while haunted by the ghost of Ethel Rosenberg.