As the players work for an Inquisitor, most missions involve rooting out heresies or matters relating to them, but the breadth of the game allows for many other missions, including wiping out dangerous gangs, gathering evidence of corruption, dealing with alien threats or eliminating rogue psykers.

[2] Each player can pick a career path for their character, which is similar to a class from other RPG systems such as Dungeons & Dragons.

[17] During late 2008 and 2009, Fantasy Flight started releasing autonomously-developed material for the Dark Heresy game: a collection of heretical factions to pit the player characters against titled Disciples of the Dark Gods, a monster manual called Creatures Anathema, and a mini-campaign in three parts dubbed The Haarlock Legacy.

Fantasy Flight also announced a manual on "radical" inquisitors (covering the most extreme factions, their tactics, equipment, and most prominent figures) and a major expansion allowing players to take their characters to the rank of interrogator, bestowed with an inquisitorial rosette, enjoying augmented prestige and able to summon more powerful allies.

On 9 September 2016 Fantasy Flight announced they would be ending their relationship with Games Workshop from 28 February 2017 for all shared products including Dark Heresy.