Steroids have accompanied other immunosuppressants throughout the history of renal transplantation. However, its permanent use has been associated with a myriad of adverse effects, which especially increase the already high cardiovascular risk of renal transplant patients. Nevertheless, steroid-sparing strategies may increase the risk of acute and chronic rejection that may worsen the fate of transplant recipients. The advent of new immunosuppressants have renovated the interest on steroid-sparing protocols, and the results of the new trials suggest that these strategies may be safe enough in view of the low rates of acute rejection and stable renal function reported. On the other hand, calcineurin inhibitors (CNIs) have been considered the cornerstone of transplant immunosuppression though their nephrotoxicity has been one of the major clinical problems in the use of these immunosuppressants. The balance between preventing immunological allograft losses and the management of CNI-related nephrotoxicity is still an issue in renal transplantation. CNI reduction or elimination may increase the risk of acute and chronic rejection. Because of these concerns, in most instances CNI have been used at conventional doses in induction and maintenance therapy. As in the case of steroid-sparing strategies, the new therapeutic arsenal has provided a new impulse in CNI-sparing regimens, with an acceptable low rate of acute rejection, well-preserved renal function and without an apparent increased risk of chronic rejection, which may pave the way for a new era in immunosuppression.