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Understanding of the natural history and treatment responsiveness of chronic hepatitis C virus (HCV) infection has evolved rapidly in recent years. Advances in HCV molecular virology and host genetics can now better predict spontaneous clearance and treatment outcomes. HCV genotype is the most important viral factor predicting interferon-alpha treatment responsiveness; HCV-1 subtype is emerging as a key determinant of the efficacy of direct acting antiviral therapy. Genome-wide association studies have recently identified several clinically important host determinants of the outcomes of peginterferon-alpha and ribavirin treatment outcome: IL28B polymorphism is associated with spontaneous clearance and treatment responsiveness; ITPA polymorphism protects against ribavirin-induced anaemia and dose reductions; genetic determinants of liver fibrosis progression rate have been proposed. In this review, we evaluate the role of viral and host genetics in the natural history and treatment outcomes of chronic HCV infection, and consider how this knowledge might help individualize clinical management in the era of DAA therapy.