Despite improvements in the prevention and treatment of acute rejection, chronic rejection remains the major cause of long-term graft loss. For renal transplantation, no convincing evidence is available that shows any immunosuppressive protocol prevents the development of chronic rejection or that any available agent ameliorates chronic rejection after it is already established; however, this is in part secondary to the relatively short follow-up period available for many of the newer immunosuppressive regimens. For liver transplantation, it appears that tacrolimus may prevent the development of chronic rejection and may salvage some grafts with preexisting chronic rejection. In the case of cardiac transplantation, the addition of an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor to standard immunosuppression based on cyclosporine A seems to effectively decrease the development of transplant vasculopathy. This article examines the utility and efficacy of current clinical therapies and promising experimental agents.