Hepatitis C is a leading etiology of liver cancer and a leading reason for liver transplantation. Although new therapies have improved the rates of sustained response, a large proportion of patients (∼50%) fail to respond to antiviral treatment, thus remaining at risk for disease progression. Although chimpanzees have been used to study hepatitis C virus biology and treatments, their cost is quite high, and their use is strictly regulated; indeed, the National Institutes of Health no longer supports the breeding of chimpanzees for study. The development of hepatitis C virus therapies has been hindered by the relative paucity of small animal models for studying hepatitis C virus pathogenesis. This review presents the strengths of human liver transplantation and highlights the advances derived from this model, including insights into viral kinetics and quasispecies, viral receptor binding and entry, and innate and adaptive immunity. Moreover, consideration is given to current and emerging antiviral therapeutic approaches based on translational research results. Liver Transpl 15:1395–1411, 2009. © 2009 AASLD.