Preacher tells the story of Jesse Custer, a preacher in the small Texas town of Annville. Custer is accidentally possessed by the supernatural creature named Genesis, the infant product of the unauthorized, unnatural coupling of an angel and a demon. The incident flattens Custer's church and kills his entire congregation.
Genesis has no sense of individual will, but since it is composed of both pure goodness and pure evil, its power might rival that of God Himself, making Jesse Custer, bonded to Genesis, potentially the most powerful being in the universe.
Driven by a strong sense of right and wrong, Custer journeys across the United States attempting to literally find God, who abandoned Heaven the moment Genesis was born. He also begins to discover the truth about his new powers. They allow him, when he wills it, to command the obedience of those who hear and comprehend his words. He is joined by his old girlfriend Tulip O'Hare, as well as a hard-drinking Irish vampire named Cassidy.
During the course of their journeys, the three encounter enemies and obstacles both sacred and profane, including: The Saint of Killers, an invincible, quick-drawing, perfect-aiming, come-lately Angel of Death answering only to "He who sits on the throne"; a disfigured suicide attempt survivor turned rock-star named Arseface; a serial-killer called the 'Reaver-Cleaver'; The Grail, a secret organization controlling the governments of the world and protecting the bloodline of Jesus; Herr Starr, ostensible Allfather of the Grail, a megalomaniac with a penchant for prostitutes, who wishes to use Custer for his own ends; several fallen angels; and Jesse's own redneck 'family' — particularly his nasty Cajun grandmother, her mighty bodyguard Jody, and the 'animal-loving' T.C.
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