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To immunologists, DNA has always had a dark side. Long before it was shown to be the genetic material, it was known to stimulate immune responses (1). When DNA is in the wrong place, it is a sign of danger. The danger can be in the form of infection where microbial DNA is sensed, or cellular damage that leaks DNA into the cytoplasm from the nucleus or mitochondria. In the latter scenario, DNA can cause havoc, provoking autoimmune conditions such as systemic lupus erythematosus. On pages 826 and 786 of this issue, Wu et al. (2) and Sun et al. (3), show that an enzyme called cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) detects cytoplasmic DNA and triggers a signaling system never before observed in metazoans, to galvanize host defense, inflammatory, and autoimmune responses.