HCV is variable because of the properties of the viral RdRp, high levels of replication, and large population sizes. The Darwinian evolution of HCV has been characterized by the emergence of the HCV genotypes, including six main types and a large number of subtypes. The study of HCV genotype epidemiology provides useful information on the worldwide HCV epidemics. The HCV genotype is an important predictor of the response to IFN-alpha-based antiviral therapy, and genotype determination is currently used to tailor treatment indications. In addition, HCV circulates and behaves in infected individuals as mixtures of closely related but distinct viral populations referred to as quasispecies. This particular nature of the virus influences its transmission, the pathogenesis of liver disease and extra-hepatic manifestations, and the outcome during and after antiviral therapy or after transplantation for HCV-related end-stage liver disease. Further studies are needed to understand better the implications of HCV quasispecies diversity in the pathophysiology of HCV infection.