When using immunosuppressant agents in renal transplantation, achieving low rejection rates while minimizing long-term toxicities (eg, nephrotoxicity and cardiovascular disease) associated with these agents is a primary goal. Strategies that reduce exposure to calcineurin inhibitors (CNIs) have demonstrated reasonable safety and efficacy in some targeted patient populations, but registry data and multicenter studies show that CNI-free regimens involving sirolimus and mycophenolate mofetil (MMF) generally have higher rejection rates and inferior graft outcomes. Longer term studies are needed to evaluate a possible learning curve with sirolimus and to study possible long-term toxicities such as wound healing, anemia, and hyperlipidemia. Converting to sirolimus and MMF after initial CNI therapy has also been studied. For example, results from the ongoing Spare the Nephron Trial demonstrate low rejection rates in stable transplant patients, short-term improvement in kidney function, and good safety results. In the future, agents such as belatacept may provide a nonnephrotoxic alternative to CNIs. Minimizing corticosteroid exposure is another worthy goal, and studies using induction protocols (eg, with lymphocyte-depleting agents or interleukin-2 receptor antagonists) and/or newer immunosuppressive agents (eg, MMF, sirolimus, and tacrolimus) have demonstrated that steroids can be withdrawn early in many patients without increasing the risk of acute rejection or long-term allograft problems. (Adv Stud Med. 2007;7(9):275-280) I mmunosuppression is now manageable in the short term but it remains a major hurdle for long-term outcomes in renal transplantation. Specifically, current combinations of immunosuppressive agents lead to markedly reduced acute rejection rates in transplantation, but they do not provide a related increase in long-term graft survival. The reasons for this include cardiovascular disease, cancer, infections, bone fractures, and other toxicities related to the immunosuppressant agents themselves. Efforts to maintain low acute rejection rates and yet minimize longer term toxicity focus not only on creation and use of novel immunosuppressant agents but also improved employment of existing agents. In particular, as reviewed here, protocols to minimize exposure to calcineurin inhibitors (CNIs) and steroids have now been tested in many settings.