In mammalian cells, the products of microbial infection are recognized by pathogen recognition receptor (PRR) proteins. Virus recognition is mediated in part by PRRs that comprise a subset of Toll-like receptors or a family of RNA helicases, the latter of which contain caspase activation and recruitment domains, both of which induce interferons alpha and beta and antiviral immune defenses. Recent studies show that PRR engagement of specific pathogen-associated molecular patterns (PAMPs) within viral products, including viral proteins and nucleic acid, is facilitated by the discrete subcellular distribution of PRRs to sites that intersect with processes of virus entry and replication. PAMP structure and the subcellular context of PRR distribution form a basis of self versus nonself discrimination during the antiviral response. Understanding the virus/host interface of PRR function and PAMP recognition will advance therapeutic strategies for immune response regulation.