Hepatitis C virus (HCV) has evolved remarkable mechanisms that favor viral persistence by interfering with host innate and adaptive immune responses. These same mechanisms are likely to contribute to resistance to exogenously administered interferon used for HCV treatment. We review the host innate and adaptive immune responses in the context of HCV infection as well as the strategies by which these responses are subverted by the virus. In addition, the contribution of host factors, such as race and insulin resistance, to interferon non-responsiveness is discussed. Our progress in understanding the molecular underpinnings of interferon treatment failure in HCV infection has resulted in several promising and novel treatment strategies for HCV treatment non-responders.