Interferons were the first of the anti-viral innate immune modulators to be characterized, initially characterized solely as anti-viral proteins [reviewed in Le Page, C., Genin, P., Baines, M.G., Hiscott, J., 2000. Inteferon activation and innate immunity. Rev. Immunogenet. 2, 374-386]. As we have progressed in our understanding of the interferons they have taken a more central role in our understanding of innate immunity and its interplay with the adaptive immune response. One of the key players in function of interferon is the interferon-inducible enzyme, protein kinase (PKR, activatable by RNA). The key role played by PKR in the innate response to virus infection is emphasized by the large number of viruses, DNA viruses as well as RNA viruses, whose hosts range from insects to humans, that code for PKR inhibitors. In this review we will first describe activation of PKR and then describe the myriad of ways that viruses inhibit function of PKR.