Immunosuppression with calcineurin inhibitors (CNI) is a major factor of chronic allograft nephropathy (CAN). When used in good conditions, proliferation signal inhibitors (PSI) could minimize CNI toxicity and improve long-term graft survival. They must not be used without CNI de novo, taking into account the high rejection rates observed for a similar or even worse renal function than with CNI. On the contrary, protocols associating CNI and PSI with subsequent withdrawal of the CNI improve renal function and decrease CAN and long-term cancer rates if the initial concentration of PSI is low. CNI/PSI associations also give good results with lower rejection rates and a better renal function, provided that low doses of CNI compared to standards are administered (i.e. 3-7 ng/m vs 8-11 ng/ml of tacrolimus) and non-nephrotoxic low circulating doses of mTORi are maintained (9 ng/ml for sirolimus and 6 ng/ml for everolimus). Finally, an alternative consisting in early substituting a CNI by a PSI is given promising results in some controlled clinical trials under way.