End-stage renal failure (ESRF) due to analgesic nephropathy is still a common clinical condition in several countries, but the prevalence in dialysis patients shows large geographical differences. The frequency of ESRF of unknown aetiology is the inverse of that linked to analgesic abuse, and data suggest that the occurrence of analgesic nephropathy may be underestimated. The study of analgesic nephropathy is difficult because the earliest damage to the kidney is a renal papillary necrosis (RPN), which cannot easily be diagnosed. Continued analgesic abuse generally leads to a progressive secondary cortical degeneration which is easier to diagnose. If analgesic abuse is stopped at an early enough stage in nephropathy, clinical symptoms stabilize or improve, and ESRF may be averted. A high incidence of upper urothelial carcinoma (UUC) is also observed in individuals with a history of analgesic abuse, but it is still not clear if the two have a related pathogenesis. Study of the mechanism of RPN in animals administered analgesics and nonsteroidal antiinflammatory drugs (NSAID) has been difficult owing to their extrarenal toxicity. Several model compounds cause identical clinical changes and have as their selective target the renal medullary interstitial cells; subsequently, other changes (including cortical and glomerular degeneration) develop as a secondary cascade. A number of mechanisms have been proposed to explain RPN (e.g., counter-current concentrating mechanism, ischaemic injury, altered prostaglandin metabolism, immunological changes), but peroxidative metabolism of papillotoxic chemicals within the interstitial cells seems to be the most likely cause. Analgesic abuse is a costly socioeconomic condition for which there is currently no clinical treatment. If it is diagnosed early enough, severe renal degeneration can be prevented. Additional epidemiological information is needed to establish the causative role of analgesics and other chemicals, in order to determine the relative risk of each. Additional animal experiments are needed in order to clarify the molecular pathogenesis of RPN and UUC, to differentiate the stages in progression to ESRF and to develop more sensitive and selective diagnostic criteria.