The introduction of cyclosporine in the early 1980s meant a decisive improvement in post-transplant outcomes for all solid-organ transplants and, in particular, it allowed heart transplantation to emerge as a viable therapeutic option for patients with end-stage cardiac failure. Many factors, including recipient and donor selection, organ preservation and the technical aspects of the transplant itself, influence post-operative outcomes following heart transplantation but the continued need to treat the recipient's immune response plays a key role in determining long-term outcomes. Thereby interactions between immunosuppressive drugs used in different combinations play an important role in patients' outcome. After more than two decades, significant controversy still exists as to the best immunosuppressive regimen for long-term maintenance. During the 1990s and 2000s, newer immunosuppressive medications, specifically, tacrolimus, mycophenolate mofetil, sirolimus, everolimus and the IL-2 receptor blockers (daclizumab and basiliximab), were introduced that allow the clinician several options to try to minimize side effects and maximize the desired therapeutic effects. The side effects involve direct organ toxicity (e.g. renal and hepatic dysfunction), metabolic disturbances, (e.g. diabetes, hyperlipidemia and hypertension), neurotoxicity, and several other significant adverse events, such as cholestasis and myelosuppression. Newer immunosuppressive drugs can impair wound healing, induce lung toxicity and produce various cytopenic states. Steroids continue to plague patients with their well-known side effects. This article reviews the current data on the benefits and risks of the various therapeutic regimens available, which are analyzed under three main themes: calcineurin inhibitor based therapies, calcineurin minimization protocols and calcineurin free regimens.