Infection with the hepatitis C virus (HCV) is a major health problem worldwide due to the associated risk of developing liver cirrhosis and its sequelae. Approximately 200 million persons are chronically infected worldwide. Furthermore, about one third of HIV-infected individuals in Europe and the US are co-infected with HCV. Currently pegylated interferon-alpha in combination with ribavirin represents the backbone of HCV-specific therapy. However, with interferon-based combination therapy sustained virologic response (SVR) is achieved in only about 50% of HCV-infected patients in clinical studies and may be even lower in clinical practice. HCV genotype and viral load are major determinants of treatment response in HCV infection. However, emerging data suggest host genetic factors also influence response to treatment. These data might hold the keys to better understand and predict outcome of HCV-specific therapy and might help to develop novel anti-HCV strategies. Here, we review the role of genetic aspects including the role of cytokines, chemokines/ chemokine receptors, and MHC alleles with respect to HCV therapy that have been elucidated so far and offer suggestions for how to use these observations as platforms for future research to further understand differential response to antiviral therapy in HCV-infected patients.