The introduction of triple-therapy regimens that include a calcineurin inhibitor (CNI), steroids, and azathioprine greatly reduced the risk of acute rejection in renal transplantation. However, the long-term use of both CNIs and steroids is associated with serious toxicities that ultimately can impact patient/graft survival. Mycophenolate mofetil (MMF), a highly effective immunosuppressant with no known nephrotoxicity, has been shown to provide benefits in preserving long-term renal allograft function relative to azathioprine. For these reasons, MMF has become an integral component of toxicity-sparing maintenance regimens that seek to minimize patient exposure to CNIs and steroids. This paper provides an overview of current strategies for reducing the toxicities associated with these agents, which include both withdrawal and avoidance regimens with or without induction therapy. Data are accumulating that toxicity-sparing regimens involving MMF are safe and decrease the risk of side effects that accompany the use of CNIs and steroids. Future studies will determine how to best implement these regimens in the renal transplant population.