Acute renal failure (ARF) occurs frequently and results in an unacceptably high morbidity and mortality. There is no currently accepted specific therapy that alters the course of ischemic ARF. Recent experimental advances and continued funding of ARF studies should allow rapid progress in the new millennium. This will require novel approaches to both basic and clinical evaluations. New experimental models and studies evaluating multiple therapies are needed. In addition, methods to identify ARF early in its course are likely to improve outcomes. Clinical studies should employ very specific definitions of ARF, outcomes evaluated, indications for renal replacement therapy, and severity of illness evaluation methods. Such studies and aggressive preventative measures will significantly improve the incidence and outcome of ARF in the 21st century.