Much has changed since the early years of liver transplantation. Improvements in post-transplant survival are largely due to more selective and less toxic immunosuppression regimens and advances in operative and perioperative care. This has allowed liver transplantation to become an extremely successful treatment option for patients with endstage liver disease. Beginning with cyclosporine, a cyclic endecapeptide of fungal origin and the first of the calcineurin inhibitors to find widespread use, immunosuppressive regimens have evolved to include additional calcineurin inhibitors, steroids, mTOR inhibitors, antimetabolites and antibodies, mostly targeting T-cell activation. This review will present currently available immunosuppressive agents used in the perioperative period of liver transplantation, as well as maintenance treatments, tailoring therapeutic strategies for specific populations, and advances in immune monitoring and tolerance.