Hepatitis C virus (HCV) re-infection of the liver graft has been recognized to be one of the most important factors that determines prognosis and outcome after liver transplantation in HCV-positive patients. Graft loss due to recurrent HCV re-cirrhosis and subsequent hepatic decompensation, which is the predominant cause of death among transplant recipients, reflects the prognostic significance of HCV re-infection. Despite better overall outcome after liver transplantation, the prognosis of HCV-infected patients has not improved during the last two decades. Recent data suggest that increased liver donor age and intensified immunosuppression of transplant patients are the most important contributors to this situation. Other prognostic factors need further confirmation to stratify risk constellations. As HCV cirrhosis has also become the leading indication for orthotopic liver transplantation, the therapeutic management of HCV re-infection is a central issue of liver transplantation. The antiviral approaches based on interferon (IFN) alpha and ribavirin combinations are still hampered by high toxicity and low efficacy. Sustained viral response rates are still as low as approximately 10-30% and further prospective clinical trials are mandatory to identify the best time point and schedule of antiviral treatment in transplant patients.