The events unfold around Jesse Custer, a tough priest from Texas. Our hero, who has lost faith in God, discovers that God has actually abandoned Heaven and is neglecting His responsibilities. Moreover, he becomes the only person capable of tracking Him down and holding Him accountable for His negligence. Accompanying Jesse on this quest to find God is his former girlfriend, a friendly vampire who prefers human blood. Hot on their trail is one of the most infamous villains: the Immortal Killing Machine, the Saint of Killers.