The outcome of a viral infection of a host involves the complex interplay of viral determinants of virulence and host resistance factors. Among the first lines of defense for the host in attempts to control viral infection are the interferons (IFNs). A large body of work has now shown that the IFNs are a family of soluble proteins that serve to mediate antiviral effects, to regulate cell growth, and to modulate the activation of immune responses. The innate antiviral activities of IFNs are exceedingly potent and rapid. It is, therefore, not surprising that so many viruses have evolved ways to either preclude the synthesis of IFNs or evade downstream antiviral events. Such evasion allows for the virus to spread before the development of a specific adaptive immune response and likely represents a pivotal determinant of virulence for the invading virus. This review describes some of the research on herpes simplex virus (HSV) that has elucidated genes involved in evasion of the IFN response. In particular, the roles of specific viral genes in resistance to the antiviral effects of PKR and RNaseL are described, along with other HSV genes and loci associated with resistance to IFN for which mechanisms have yet to be described.