Recognition of DNA is an evolutionarily highly conserved mechanism of immunity. In mammals, the cGAS-STING pathway plays a central role in coupling DNA sensing to the execution of innate immune mechanisms, both in contexts of infection as well as in noninfectious settings of cellular stress and injury. The indiscriminate ability of double-stranded DNA (dsDNA) to activate cGAS challenges our understanding on how engagement of this pathway is prevented on genomic selfDNA under homeostatic conditions. Here, we review recent discoveries on the regulation of cGAS on chromatin and we discuss implications for cGASdependent inflammatory phenotypes. We close by highlighting emerging developments on the role of nuclear cGAS and related open questions for future research.