Detection of intracellular DNA triggers activation of the stimulator of IFN genes–dependent IFN-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses. However, chronic activation of this pathway is implicated in autoimmunity. Mutations in TREX1, a 3′ repair exonuclease that degrades cytosolic DNA, cause Aicardi–Goutières syndrome and chilblain lupus. Trex1−/− mice develop lethal, IFN-driven autoimmune disease that is dependent on activation of the ISD pathway, but the DNA sensors that detect the endogenous DNA that accumulates in Trex1−/− mice have not been defined. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP–AMP synthase (cGAS). In this study, we show that Trex1−/− mice lacking cGAS are completely protected from lethality, exhibit dramatically reduced tissue inflammation, and fail to develop autoantibodies. These findings implicate cGAS as a key driver of autoimmune disease and suggest that cGAS inhibitors may be useful therapeutics for Aicardi–Goutières syndrome and related autoimmune diseases.