Natural Killer (NK) cells account for the majority of innate immune cells in the human liver (the primary site of HCV replication). CD3–CD56+ NK cells are significantly increased in the liver compared to the peripheral blood although this becomes especially evident in chronic HCV infection. NK cells have been implicated in all stages of HCV infection in both genetic and functional studies. This role may be either direct, by targeting infected hepatocytes, or indirect by influencing other key immunocytes such as dendritic cells (DCs) or T cells. Hepatotropic viruses such as HCV induce production of type I Interferon (IFN) by hepatocytes and other cells in the liver, which in turn promotes infiltration of NK cells in virus infected livers. Production of type I IFN and other cytokines (including Interleukin (IL)-12, IL-15, and IL-18) by hepatocytes activates NK cells and induces IFN-γ production by them, which recruits activated T cells to the liver. It has been shown in animal models that depletion of NK cells before hepatotropic viral infection leads to inhibition of a virus-specific T cell response, as well as inhibition of liver injury. It is possible that an adequate NK cell response may control HCV infection, even in the absence of virus-specific immune responses. NK cells have direct antiviral effects which are mediated by direct cytolytic (e.g., TRAIL or perforin mediated) or non-cytolytic (e.g., IFN-γ mediated) effector functions. Understanding the mechanisms by which HCV is successfully eradicated is especially important for therapeutic and vaccination strategies.