Reverend Jesse Custer has destroyed the fortress and the conspiracy plans of the powerful Grail and freed his hard-drinking vampire friend Cassidy from their clutches. Now he wants to return to his girlfriend Tulip O'Hare and continue the search for God—if Tulip forgives him for not taking her along on his little rescue mission. But before he can confront God, Jesse must make contact with Genesis, the offspring of a liaison between angel and demon, who has merged with his soul. For this, he needs a truly spiritual mediator, an expert in black magic. Fortunately, Cassidy knows a voodoo priest in New Orleans who could help access Genesis's hidden memories. Unfortunately, there is also a cult of bloodthirsty wannabe vampires there who are after Cassidy's head.