Preacher tells the story of Jesse Custer, a down-and-out preacher in the small Texas town of Annville. Custer was accidentally possessed by the supernatural creature named Genesis in an incident which killed his entire congregation and flattened his church.Genesis, the product of the unauthorized, unnatural coupling of an angel and a demon, is an infant with no sense of individual will. However, as it is composed of both pure goodness and pure evil, it might have enough power to rival that of God himself. In other words, Jesse Custer, bonded to Genesis, may have become the most powerful being in the whole of living existence.Custer, driven by a strong sense of right and wrong, goes on a journey 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, which allow him to command the obedience of those who hear 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 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.