Distinct families of germline-encoded pattern recognition receptors can sense both microbial and endogenous nucleic acids. These DNA and RNA sensors include endosomal TLRs and cytosolic sensors upstream of stimulator of type I IFN genes (STING) and MAVS. The existence of overlapping specificities for both foreign and self nucleic acids suggests that, under optimal conditions, the activity of these receptors is finely tuned to effectively mediate host defense yet constrain pathogenic self-reactivity. This equilibrium becomes disrupted with the loss of either TLR9 or STING. To maintain immune protection, this loss can be counterbalanced by the elevated response of an alternative receptor (s). Unfortunately, this adjustment can lead to an increased risk for the development of systemic autoimmunity, as evidenced by the exacerbated clinical disease manifestations of TLR9-deficient and STING-deficient autoimmune-prone mice. These studies underscore the delicate balance normally maintained by tonic signals that prevent unchecked immune responses to nucleic acids released during infections and cellular duress or death.