When a virus or bacteria comes calling, protein “sensors” in your cells can detect the invader’s DNA and activate inflammatory responses to prevent infection. One such sensor is cGAS (cyclic GMP-AMP synthase). Normally, cGAS is an asset – something you definitely want to be working for you. However, abnormal responses to intracellular DNA can lead to hyper-inflammatory or autoimmune disorders such as lupus. Turning cGAS off may actually help treat this disease. Manuel Ascano Jr., Ph.D., and colleagues now report the discovery of a class of compounds that can inhibit cGAS. One “chemically improved” compound, RU.521, showed potent and selective inhibition of cGAS activity and lowered inflammatory signaling molecules in immune cells in a mouse model of an autoimmune disease.