The central issue in organ transplantation remains suppression of allograft rejection. Thus, development of immunosuppressive drugs is the key to successful allograft function. New immunosuppressive drugs were introduced on the basis of their ability to reduce the incidence of acute rejection and to demonstrate shortterm outcomes at least equivalent to those achieved with the use of established immunosuppressive therapy. Although short-term renal allograft survival has improved since the introduction of calcineurin inhibitors (CNIs), long-term renal allograft survival remains a major concern, with chronic allograft nephropathy (CAN) being the principal cause of renal allograft loss after the first year. CAN has traditionally been viewed as the result of repeated low-grade immune responses directed against allogeneic tissue, but recent evidence indicates that nonimmunological or alloantigen-independent factors also contribute to its pathogenesis. CNI nephrotoxicity occurs soon after initiation of therapy, is more clearly dose-dependent. This scenario presents a clear need for new strategies that produce adequate immunosuppression to prevent acute rejection and simultaneously reduce adverse effects associated with CNI-related therapies. To obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on CNIs.