End-stage liver disease associated with hepatitis C virus (HCV) infection has become the leading indication for liver transplantation worldwide. The new transplant liver is infected in nearly all patients, but the disease progression is highly variable. Although short-term survival appears to be similar to that in other causes of liver failure, progression to HCV-related cirrhosis is estimated to reach 20–30% at 5 year follow-up. Identification of factors that influence disease progression is important to optimize results of current treatment. This review summarizes the natural history, therapeutic options and future therapeutic strategies aimed at the induction and reinforcement of an adequate virus-specific CD4+ T cell response.