HCV infection is an exponentially growing health burden worldwide, with an estimated 170 million people infected. Although therapies for HCV are continually improving, there remain a considerable proportion of patients who do not achieve viral eradication and develop liver disease. Natural killer (NK) cells are crucial for T-cell activation and are one of the first-line sentinel cell responders to viral infection. A recent explosion in studies exploring the role of NK cells in HCV infection has yielded important mechanistic information and intriguing potential therapeutic options for HCV infection. This review provides a general overview of normal NK cell function and outlines some of the important mechanisms characterizing the immune interplay between NK cells and HCV infection.