The nonnarcotic analgesics have been implicated as a significant cause of chronic renal failure worldwide. Epidemiologic studies of habitual abuse and necropsy studies show a strong relationship between the two. Animal studies designed to elucidate underlying mechanisms have been hampered because the lesion occurs infrequently and only after very high doses are given for prolonged periods; however, the Fischer 344 and Wistar rats appear to be more sensitive, and substantial new information should be forthcoming. In this review, some of the evidence for the possible mechanisms of papillary necrosis are presented: prostaglandin inhibition, reduction or redistribution of renal blood flow, direct cellular injury, free radical formation, and immunologic injury. At present, most data support prostaglandin inhibition and reduction or redistribution of renal blood flow, but direct cellular injury also appears to be very important.