Induction of tolerance, which obviates the need for maintenance immunosuppression following organ transplantation remains elusive. In cardiac transplantation, ongoing immunosuppressive therapy is essential to ensure long-term graft survival. Although drug regimens have substantially improved in recent years, their adverse effects continue to cause significant morbidity and affect quality of life. Newer immunosuppressive therapies have been effective at reducing allograft rejection rates in the short term but long term outcomes have changed little in the last two decades. Minimization of immunosuppression requires appreciation of the potential consequence. High risk patients in particular need to be identified and excluded from low intensity immunosuppressive regimens. A variety options exist for lowering of immunosuppression and steroid weaning has now become common practice with about 40% of all cardiac transplant recipients remaining steroid free in the long term. Minimization of calcineurin inhibitor exposure may be achieved with concurrent use of the more potent anti-proliferative agents mycophenolate mofetil and sirolimus. Patients require close monitoring for rejection during weaning. In addition to the conventional clinical parameters which include therapeutic drug monitoring, endomyocardial biopsy and echocardiography, newer techniques for monitoring hold future promise. These include detection of circulating alloantibodies and quantitative measurement of the net state of immunosuppression (Cylex). However, the efficacy of these modalities requires further investigation.