Basically, it's about a preacher, Jesse, who, after gainining the ability to verbally command people to do anything he wants, decides to trek across the country to catch God who has abandoned his post in heaven, to make him pay for that and his utter disregard towards humankind. He's also joined by his old girlfriend, who's a part-time hitman and Cassidy, a vampire.
There are also people/organizations after Jesse. First, his grandmother and her band of merry southern religious zealots, a centuries old organization whose purpose is to keep the Christ bloodline alive and the Saint Of Killers, a 7-foot Clint Eastwood-type cowboy who the angels currently in-charge of Heaven, sent after Jesse to get back Genesis, the child of a demon and an angel, who after escaping his imprisonment in heaven, bonded with Jesse, giving him the aformentioned ability to command people and also full knowledge of heaven and God.