The history, pharmacokinetics, mechanisms of action, and experimental as well as clinical data on the immunosuppressive potential of the novel drugs tacrolimus (FK506), sirolimus (rapamycin), mycophenolic acid (mycophenolate mofetil), and leflunomide (and its malononitriloamide analogues) are provided. Novel approaches with the following conventional immunosuppressants are outlined: methotrexate, aerosolized immunosuppression and the implementation of steroid taper. Total lymphoid irradiation and photopheresis for treatment of recurrent rejection are also discussed.