Treatment of hepatitis C after liver transplantation can be challenging as graft rejection and graft hepatitis caused by hepatitis C virus (HCV) may be difficult to distinguish. Immunosuppressive medications may significantly alter the course of hepatitis C in liver transplant recipients. Moreover, single substances have been shown to display antiviral effects in vitro while others are believed to have antifibrotic properties. This review summarizes the modes of action of different classes of immunosuppressive drugs used after liver transplantation and discusses pros and cons of individual drugs in the setting of HCV infection. No definite recommendation for an optimal immunosuppressive regimen can be given at this stage. The most important lesson learned during the last two decades is that acute rejection episodes have to be avoided in particular in hepatitis C since these are associated with reduced graft and patient survival. Further trials are urgently needed to clarify the role of different immunosuppressive compounds in hepatitis C after transplantation.