Preacher tells the story of Jesse Custer, a 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.
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. 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.