Current strategies to limit the extent of injury in acute renal failure are based on extensive studies that identified cellular and molecular mechanisms of acute kidney injury. Despite successes in various animal models, translation to human studies has failed or studies are inconclusive. This review describes past failures and barriers to successful clinical trials. It also focuses on promising preclinical studies using novel compounds that currently are in or close to human investigation. Implementation of previous or novel compounds in well-designed clinical trials provides hope for the successful treatment of this devastating disorder.