Chronic allograft nephropathy, characterized by interstitial fibrosis and tubular atrophy, is still a major cause of graft loss after kidney transplantation. The complex pathophysiology of chronic allograft nephropathy is still poorly understood, and could be clarified by a more systematic performance of implantation and protocol biopsies of the renal allograft. This review highlights the contribution of implantation and protocol biopsies to our current knowledge of the complex interaction of multiple processes, ultimately leading to the development of interstitial fibrosis and tubular atrophy in the transplanted kidney. In addition, the safety and the limitations of protocol biopsies are discussed, as well as potential future directions for clinical practice and clinical research.