Many novel immunosuppressive agents are under active clinical investigation. In addition, creative approaches are being developed for the use of established immunosuppressive agents, with the goal of minimizing immunosuppression as early as possible posttransplantation. The hope is that these approaches will minimize the toxicity of these agents without sacrificing efficacy. Evidence suggests that the nephrotoxicity of calcineurin inhibitors can be reduced using these approaches. The introduction of newer immunosuppressive agents, including the proliferation signal inhibitors, raises the possibility that some of the long-term scourges of cardiac transplantation, including cardiac allograft vasculopathy and malignancy, can be ameliorated. Finally, costimulatory pathway inhibitors and other new immunosuppressive agents offer hope that all these goals can be accomplished with very low long-term maintenance immunosuppression.