Chronic allograft nephropathy (CAN) is the first cause of graft failure. Since graft survival has improved and the incidence of rejection decreased, these outcomes cannot be employed as primary efficacy variables in clinical trials due to the need for a large sample size. The presence of CAN in protocol biopsies is an independent predictor of graft survival. Thus, it has been proposed that chronic lesions in protocol biopsies be considered a primary efficacy variable. Power calculations have confirmed this hypothesis, especially if CAN is evaluated using a morphometric technique. Moreover, it has been demonstrated that in vivo glomerular number (Ng) can be estimated by combining a protocol biopsy with magnetic resonance imaging. Ng correlates with graft function in stable grafts. Taken together, these data suggest that protocol biopsies constitute a fundamental tool to improve the design of clinical trials and to define parameters that are crucial to the understanding of mechanisms leading to CAN.