The life of any organism depends on the ability of cells to detect and to respond to pathogens. In order to detect the immense variety of pathogenic entities, the innate immune system of mammals has evolved arange of distinct sensing strategies. One major mechanism is based on the recognition of microbial DNA - an invariant and highly immunogenic pathogen-associated molecular pattern. Host cells, however, contain abundant sources of self-DNA. In the context of cellular damage or metabolic derangement, “out-of-thecontext” self-DNA can elicit potentially damaging inflammatory responses. Our research focuses on the socalled cGAS-STING system - an evolutionary highly conserved innate DNA sensing system. On DNA binding, cGAS is activated to produce a second messenger cyclic dinucleotide (cyclic GMP-AMP), which stimulates the adaptor protein STING to induce innate immune responses. While this process was originally discovered as a crucial component of immune defense against pathogens, recent work has elucidated a pathogenic role for innate DNA sensing in a variety of sterile inflammatory diseases. In this talk I will discuss recent findings on cellular mechanisms that regulate cGAS activity and present work on the pharmacological manipulation of aberrant cGAS-STING signaling in the context of inflammatory diseases.