The advent of modern immunosuppressive agents is arguably the single most important factor that has allowed liver transplantation to advance in the past several decades from a dubious and dangerous venture to the treatment of choice for end-stage liver disease. During the past two decades, a large array of immunosuppressants have greatly expanded the armamentarium used by transplant physicians and surgeons to prevent and treat liver allograft rejection. The availability of these drugs has resulted in the excellent short-term and long-term outcomes achieved in liver transplantation. However, these drugs continue to lack specificity and are associated with acute and chronic toxicities. Although the liver is considered a relatively tolerogenic organ, we have yet to attain the “Holy Grail” of transplantation, that is, transplantation tolerance, in a consistent manner. Thus, the liver transplant recipient is still being sentenced to a lifelong course of chronic immunosuppression. Small molecules, biologic agents such as antibodies and fusion proteins, and corticosteroids continue to play a central role in immunosuppressive regimens used in liver transplantation. In addition several novel immunosuppressive agents have been used in preclinical and clinical trials that show promise for use in the near future. We review current immunosuppressive medications and describe the new developments that are on the horizon.