Mutations causing dysregulated interferon signaling underlie systemic autoinflammatory disorders such as Aicardi-Goutières syndrome. Raphaela Goldbach-Mansky and colleagues (N. Engl. J. Med. 371, 507–518, 2014) now show that a rare syndrome characterized by early-onset systemic inflammation, cutaneous vasculopathy and lung inflammation is caused by de novo activating mutations in TMEM173, which encodes an activator of interferon signaling called STING. Suspecting a genetic basis for this early-onset inflammatory disease, the authors performed exome sequence on an affected individual and her unaffected parents and identified a de novo missense mutation in TMEM173 that altered a conserved residue in STING. They then performed targeted sequencing in five unrelated individuals with similar clinical manifestations and identified de novo missense mutations in TMEM173 in all five cases. Next, they analyzed peripheral blood from affected individuals and observed a strong interferon response signature. They further assessed the activity of the mutant proteins and found that they resulted in strong activation of an interferon-sensitive reporter. Together, these findings show that gain-of-function mutations in TMEM173 cause an inflammatory syndrome marked by vascular and pulmonary manifestations and expand the range of human diseases caused by dysregulated interferon signaling.