Herpesvirus infection leads to the rapid induction of an innate immune response. A central aspect of this host response is the production and secretion of type I interferon. The current model of virus-mediated interferon production includes three stages: sensitization, induction, and amplification. A key mediator of all three stages is the cellular transcription factor interferon regulatory factor 3 (IRF3). Although the precise details of IRF3 activation and interferon production in response to herpesvirus infection are still being elucidated, viral proteins that block components of the interferon pathway, particularly IRF3, have been identified and characterized. In vivo studies have shown that in addition to type I interferon, interleukin-15 (IL-15) and natural killer (NK) cells also play an important role in mediating resistance to herpesvirus infection. Recent investigations have demonstrated a strong association between IRF3, interferon, IL-15, and NK cells. This review will focus on herpesvirus-mediated induction of innate immunity, the central role of the type I interferon response and mechanisms used by herpesviruses to block host antiviral immunity.