The series was created by writer Garth Ennis and artist Steve Dillon, with painted covers by Glenn Fabry.

Custer is accidentally possessed by the supernatural creature named Genesis, the infant of the unauthorized, unnatural coupling of an angel and a demon.

Driven by a strong sense of right and wrong, Custer journeys across the United States attempting to literally find God, who abandoned Heaven the moment Genesis was born.

During the course of their journeys, the three encounter enemies and obstacles both sacred and profane, including The Saint of Killers, an invincible, quick-drawing, perfect-aiming, come-lately Angel of Death answering only to "He Who Sits On The Throne"; a disfigured suicide attempt survivor turned rock-star named Arseface; a serial-killer called the 'Reaver-Cleaver'; The Grail, a secret organization controlling the governments of the world and protecting the bloodline of Jesus; Herr Starr, primary enforcer for The Grail, a megalomaniac with a penchant for prostitutes, who wishes to use Custer for his own ends; several fallen angels; and Jesse's own redneck family — particularly his nasty Cajun grandmother, her mighty bodyguard Jody, and the Zoophilic T.C.

Ennis approached Kevin Smith and Scott Mosier to help finance the film under their View Askew Productions banner.

[4] In September 2001, the two companies announced Preacher had been greenlighted to commence pre-production, with filming to begin in November and Talalay still directing Ennis' script.

[9] With the full-length film adaptation eventually abandoned with budgetary concerns,[7] HBO announced in November 2006 that they commissioned Mark Steven Johnson and Howard Deutch to produce a television pilot.

"[11] By August 2008, new studio executives at HBO decided to abandon the idea, finding it too stylistically dark and religiously controversial.

[15] On November 18, 2013, Bleeding Cool confirmed that Seth Rogen and Evan Goldberg had developed the series pilot with Sam Catlin, and that it would be distributed by Sony Pictures Television.

[16][17] On February 7, 2014, it was made public that AMC was officially developing the series to television based on the pilot written by Seth Rogen and Evan Goldberg.

[18] Preacher was slated to premiere mid to late 2015, as announced by Seth Rogen, with the script for the series complete and the pilot ordered by the studio.

[22][23] On April 17, 2015, Seth Rogen tweeted that Dominic Cooper was cast in the role of Jesse Custer, Joseph Gilgun as Cassidy, Ruth Negga as Tulip O'Hare, Ian Colletti as Arseface, and W. Earl Brown as Sheriff Hugo Root.

[27] The character Yorick from Y: The Last Man, has a Zippo lighter with the words "Fuck Communism" engraved, identical to the one owned by Jesse Custer in Preacher.

[29] In February 2009, an older now-human Proinsias Cassidy appears in a epilogue cameo role in the fourth volume of Garth Ennis' first ongoing comic book series after Preacher, the DC Comics (WildStorm)/Dynamite Entertainment series The Boys – "We Gotta Go Now" – in the twenty-seventh issue overall, depicted as a former friend and sponsor of Billy Butcher working as a bartender, clearing out his bar on St. Patrick's Day so that Billy can drink in peace while waiting for Wee Hughie Campbell.