Rev. Jesse Custer is a badass Texas preacher who, after losing his faith, learns that God has left heaven and forsaken his duties. Jesse becomes the only one who is able to track God down and hold him responsible for his abdication. Tulip O'Hare, Jesse's beer-guzzling vampire ex-girlfriend, accompanies him on his quest for answers. But the story doesn't end there: The Saint of Killers, an immortal killing machine and Western lone gunman type, is hot on their trail with his sights set on Jesse.