The pronounced radiosensitivity of renal tissue limits the total radiotherapeutic dose that can be applied safely to treatment volumes that include the kidneys. The incidence of clinical radiation nephropathy has increased with the use of total-body irradiation (TBI) in preparation for bone marrow transplantation and as a consequence of radionuclide therapies. The clinical presentation is azotemia, hypertension, and, disproportionately, severe anemia seen several months to years after irradiation that, if untreated, leads to renal failure. Structural features include mesangiolysis, sclerosis, tubular atrophy, and tubulointerstitial scarring. Similar changes are seen in a variety of experimental animal models. The classic view of radiation nephropathy being inevitable, progressive, and untreatable because of DNA damage-mediated cell loss at division has been replaced by a new paradigm in which radiation-induced injury involves not only direct cell kill but also involves complex and dynamic interactions between glomerular, tubular, and interstitial cells. These serve both as autocrine and as paracrine, if not endocrine, targets of biologic mediators that mediate nephron injury and repair. The renin angiotensin system (RAS) clearly is involved; multiple experimental studies have shown that antagonism of the RAS is beneficial, even when not initiated until weeks after irradiation. Recent findings suggest a similar benefit in clinical radiation nephropathy.