Beginning several months after the events in Blade Runner, Deckard has retired to an isolated shack outside the city, taking the replicant Rachael with him in a Tyrell transport container, which slows down the replicant aging process. He is approached by a woman who explains she is Sarah Tyrell, niece of Eldon Tyrell, heiress to the entire Tyrell Corporation and the human template (templant) for the Rachael replicant. She asks Deckard to hunt down the "missing" sixth replicant. At the same time, the human template for Roy Batty hires Dave Holden, the blade runner attacked by Leon, to help him hunt down the man he believes is the sixth replicant - Deckard.

Holy Fire is the story of an old woman who has gained a second youth—in a world in which radical life extension is available through highly intrusive technological means—and who has an ontological transformation as a result.

At the beginning of the novel, the main character, Hiro Protagonist, discovers the name of a new pseudo-narcotic, "Snow Crash", being offered at an exclusive Metaverse nightclub. Hiro's friend and fellow hacker Da5id falls victim to Snow Crash's effects, which are apparently unique in that they are experienced in the Metaverse and also in the physical world. Hiro uses his computer hacking, sharp cognitive skills, and sword-fighting to uncover the mystery of "Snow Crash"; his pursuit takes the reader on a tour of the Sumerian culture, a fully instantiated anarcho-capitalist society, and a virtual meta-society patronized by financial, social, and intellectual elites. As the nature of Snow Crash is uncovered, Hiro finds that self-replicating strings of information can affect objects in a uniform manner even though they may be broadcast via diverse media, a realization that reinforces his chosen path in life.