Preacher follows Jesse Custer, a hard-drinking, chain-smoking preacher who has lost his faith. After being possessed by a mysterious entity named Genesis—the offspring of an angel and a demon—Jesse gains the power of 'The Word,' which allows him to command anyone to do anything he says. He embarks on a supernatural journey across America to find God, who has abandoned Heaven. Accompanied by his ex-girlfriend Tulip O'Hare and an Irish vampire named Cassidy, Jesse finds himself caught in a violent conflict between Heaven, Hell, and various sinister forces. As they traverse the country, they are pursued by the Saint of Killers, an unstoppable, supernatural assassin sent from Hell to eliminate Jesse and reclaim the power of Genesis.