In the last 5 years the use of a multicenter approach has helped to define acute liver failure (ALF) in the United States. Drug-related hepatotoxicity comprises more than 50% of cases of ALF, including acetaminophen toxicity (40%) and idiosyncratic drugs (approximately 12%). Nearly 20% of cases remain of unknown etiology. Outcome of ALF is determined by etiology; by the degree of hepatic encephalopathy present on admission; and by complications, principally infection. More than 43% survive without a transplant, 28% die, and 29% undergo liver transplantation. Liver support machines have had no impact on this condition to date. A trial of N-acetylcysteine for the treatment of ALF not related to acetaminophen toxicity is underway. Future research in ALF in the United States should focus on limiting the number of cases related to drugs, searching for causes of the indeterminate cases, and developing more effective temporary liver support.