Significance Several chronic inflammatory conditions have recently been shown to depend on abnormally high activity of the signaling protein stimulator of IFN genes (STING). These conditions include examples from systemic lupus erythematosus, Aicardi–Goutiéres syndrome, and STING-associated vasculopathy with onset in infancy. The involvement of STING in these diseases points to an unmet demand to identify inhibitors of STING signaling, which could form the basis of anti-STING therapeutics. With this report, we identify distinct endogenously formed lipid species as potent inhibitors of STING signaling—and propose that these lipids could have pharmaceutical potential for treatment of STING-dependent inflammatory diseases.