Hepatitis C virus (HCV) infection is a global health problem and a leading cause of end-stage liver disease and hepatocellular carcinoma. Treatment of HCV infection with pegylated interferon-alpha and ribavirin can eradicate chronic HCV infection in approximately 50% of patients infected with high viremia of HCV genotype 1, and spontaneous viral clearance was observed in approximately 30% of individuals with acute infection. These findings were strongly expected to reflect variations of the host genome. Significant breakthrough by the genome-wide association study (GWAS) approach led to the discovery of genetic polymorphisms playing a major role in the evolution of infection, as well as on treatment response and adverse effects. Herein, we present current evidence with regard to the relationship between host variations and clinical outcome of hepatitis C, and focus on the potential clinical implications with respect to tailor-made therapy for chronic hepatitis C.