The subject of transplant immunosuppression has generated significant interest in recent years. Excellent immunosuppression, advances in surgical technique, post-transplantation care, and infection control have resulted in excellent outcomes. There is widespread support for the notion that the fundamental objective in transplant immunology should be the achievement of specific graft tolerance. However, until this objective evolves into reality, investigators are in search of the “ideal immunosuppressant”, which should target predominantly the immune system with minimal consequences for other tissues and minimal metabolic, cardiovascular and renal complications. While immunosuppressants have been associated with a tremendous trade-off in terms of morbidity, new agents have provided the investigators with the opportunity to formulate strategies that employ combination therapies with the goal of decreasing doses of individual agents and minimizing their toxicities. Multiple small studies have addressed the issue of minimizing immunosuppressants, but there is a need for well-designed clinical trials which should evaluate protocols that will reduce acute rejection, as well as chronic allograft nephropathy. They should address methods to identify subsets of patients who would maximally benefit from avoidance or withdrawal of steroids or calcineurin inhibitors. Other promising areas of research include tolerance studies among the sensitized recipients, and development of optimal immunosuppression based on genotype. In general, future trials must include a more diverse population of recipients, particularly the immunologically high risk groups.