Prevention of chronic allograft dysfunction is currently one of the main goals in renal transplantation for the improvement of kidney graft survival. For this purpose, refinements in immunosuppressive regimens, both controlling alloimmune responses and avoiding calcineurin inhibitor (CNI)-derived nephrotoxicity, are mandatory. The majority of trials aiming to avoid CNI-related nephrotoxicity have only reported short-term data, with different rates of acute rejection depending on the strategy performed. First attempts of CNI-free strategies in micophenolate mofetil-based regimens showed unsatisfactory results in terms of increased acute rejection events. With the advent of mammalian target of rapamycin inhibitors, a new optimistic perspective seemed to appear. Despite an increased risk of rejection, better graft function and graft parenchyma preservation seem to be associated with such a strategy, at least in the short term, with a potential benefit in terms of less cardiovascular-related adverse events and malignancies. New biological agents such as belatacep have been developed as another interesting strategy for CNI avoidance. Importantly, in any case, longer-term analyses of all these CNI-avoidance strategies are warranted in order to confirm whether persistent immune-mediated graft damage can be safely overcome.