Virus infection elicits potent responses in all cells intended to contain virus spread before intervention by the adaptive immune system. Central to this process is the virus-elicited production of type I interferons (IFNs) and other cytokines. The sensors involved in coupling recognition of viruses to the induction of the type I IFN genes have only recently been uncovered and include endosomal and cytosolic receptors for RNA and DNA. Here, we review their properties and discuss how their ability to recognize the unusual presence of atypical nucleic acids in particular subcellular compartments is used by the body to detect virus presence.