Calcineurin inhibitors remain the mainstay of immunosuppression in liver transplantation but are associated with important side effects such as diabetes, hypertension and nephrotoxicity which can influence quality of life and survival rates. A variety of non-calcineurin inhibitors have been used in liver transplantation, either during induction immunosuppression in an attempt to delay the introduction of calcineurin inhibitors or during maintenance immunosuppression with reduced dose calcineurin inhibitors to minimize calcineurin inhibitor toxicity while preserving hepatic allograft function. With few exceptions, single agent immunosuppression with non- calcineurin inhibitors has not been universally practiced outside of clinical trials due to unacceptably high rates of hepatic allograft rejection. Although several single center studies have reported encouraging results with these new agents when used with reduced dose calcineurin inhibitors, large, randomized studies are eagerly awaited. Furthermore, as the impact of these newer agents on the recurrence of hepatitis C continues to evolve, clinicians need to be prudent with their use until data from controlled studies is available. This article will review currently used immunosuppressants in liver transplantation, novel therapies in development and the impact of these medications of the recurrence of hepatitis C after liver transplantation.