Progress in transplant immunosuppression has occurred in recent years with the emergence of new chemical agents along with new monoclonal antibodies. In this review, recent works are described in tacrolimus/mycophenolate mofetil/sirolimus-based immunosuppression, and also in anti-IL2R monoclonal antibody-based induction. In the light of recent multicenter and single-center clinical trials, several lessons have been learned: less acute rejection, no amelioration of patient/graft survival at short term, and significant side effects are seen with these new agents. On the other hand, several issues need to be solved or confirmed in the future by designing new trials: Are surrogate or other end points for efficacy other than patient/graft survival needed? Will these new agents avoid induction therapy? Will these new agents allow further reduction or replacement of steroids? Could these new agents treat or prevent chronic graft dysfunction? Could the use of nephrotoxic calcineurin inhibitors be limited or avoided? Is individualization of immunosuppressive therapy feasible? In our view, new trials have raised more questions that they have answered. Answering those questions is an exciting challenge for the new millennium.