The innate immune system senses perturbations in homeostasis by recognizing specific microbial or endogenous molecules that indicate infection, injury, or tissue dysfunction. One such molecule is DNA, which can be derived from several classes of microbes or from host cell nuclei or mitochondria. A panoply of innate immune sensors for DNA are now identified. Until now, a system of DNA sensors strategically located in cell compartments free of resident DNA (e.g., cytoplasm) seemed a logical mechanism to detect infection or cell injury. However, the recent identification of a nuclear DNA sensor (1) has raised several questions about how the immune system discriminates non-self from self and generates distinct inflammatory responses. We propose that multiple DNA sensors have evolved not only to ensure that the innate immune system detects foreign or mislocalized DNA, but to provide a mechanism for cells to assess the extent of organismal danger and deliver an appropriate immune response.