Interstitial fibrosis (IF) and tubular atrophy (TA) are integral parts of chronic allograft dysfunction and represent in the new classification a separate entity with or without the identification of a specific etiology. Loss of kidney graft function with IF/TA is one of the causes of most kidney allograft losses. Despite progress in immunosuppression, chronic allograft dysfunction remains the main clinical challenge for improving long-term graft survival. The sustained damage to the allograft does not represent a single entity but the summated effects of tissue injury from several pathogenic insults, as well as the kidney's healing response, modified by alloimmunity and immunosuppression. A major challenge in the future of kidney transplantation includes the study of chronic allograft dysfunction pathogenesis to identify early markers of disease progression, as well as potential therapeutics pathways.