Liver transplantation in patients with active hepatitis C virus (HCV) infection is followed by almost universal recurrence of viral infection. The control of HCV infection has been characterized largely in terms of the HCV-specific function of T-lymphocytes and the adaptive immune response. Emerging data suggest that components of the innate immune system, including natural killer cells, have a central role in determining the nature of posttransplant HCV infection and the likelihood of response to antiviral therapy. This review examines the emerging evidence implicating innate immunity in the pathogenesis of posttransplant HCV infections and the potential therapeutic implications of these observations.