Chronic allograft dysfunction is associated with a variety of fibrosing/sclerosing changes in the allograft. Fibrosis is multifactorial, a final pathway following varying types of injury. Using a range of diagnostic criteria, the pathologist can and should define specific lesions enabling identification of pathogenic processes affecting the allograft. Although some cases remain ‘interstitial fibrosis and tubular atrophy, no specific cause’, specific diagnoses can be made in most cases. Drug toxicity, bacterial or viral infection, hypertension, obstruction, recurrent or de novo renal diseases, and acute and chronic cell- and/or antibody-mediated rejection can be diagnosed in this setting. Of particular concern is a combination of persistent inflammation and fibrosis, which has repeatedly been shown to be correlated with poor graft outcomes. Identification of ongoing activity, and the stage of evolution of fibrosis/sclerosis provides important diagnostic and therapeutic information for patient management. Histological, immunohistological, ultrastructural, and molecular studies may be needed to adequately assess the kidney in the setting of chronic allograft dysfunction. Protocol biopsies may provide diagnostic insights in early stages of late graft deterioration, or even before evident dysfunction develops.