In Skullgirls, players engage in combat against one another, with teams of one, two, or three characters attempting to knock out their opponents or have the most cumulative health when time runs out. The setting of the game revolves around the "Skull Heart", an artifact which grants wishes for women. If a wisher with an impure soul uses the Skull Heart, she is transformed into the next "Skullgirl", a monster bent on destruction.