Calcineurin inhibitors, such as cyclosporine and tacrolimus, have been available for almost 20 years. Although these drugs are highly effective and represent the mainstay of transplant immunosuppression, they are associated with acute and chronic nephrotoxicity. Acute nephrotoxicity, which occurs in the early period after transplantation, leads to a higher rate of dialysis, and chronic nephrotoxicity may eventually result in graft loss. Acute and chronic nephrotoxicity is becoming more common as the use of marginal kidneys for transplantation increases. Two recently available immunosuppressive agents, mycophenolate mofetil and sirolimus (rapamycin), have no nephrotoxicity. The use of these drugs in combination with other agents has led to the development of new paradigms of immunosuppressive therapy. This paper reviews the results of clinical trials that have investigated these new approaches to immunosuppression in renal transplant recipients.