Cells of the innate immune system are rigged with sensors that detect nucleic acids derived from microbes, especially viruses. It has become clear that these same sensors that respond to nucleic acids derived from damaged cells or defective intracellular processing are implicated in triggering diseases such as lupus and arthritis. The ways in which cells die and the concomitant presence of proteins and peptides that allow nucleic acids to re‐enter cells profoundly influence innate immune responses. In this review, we briefly discusses different types of programmed necrosis, such as pyroptosis, necroptosis, and NETosis, and explains how nucleic acids can engage intracellular receptors and stimulate inflammation. Host protective mechanisms that include compartmentalization of receptors and nucleases as well as the consequences of nuclease deficiencies are explored. In addition, proximal and distal targets in the nucleic acid stimulation of inflammation are discussed in terms of their potential amenability to therapy for the attenuation of innate immune activation and disease pathogenesis.