Fulminant hepatic failure (FHF) remains a rare but devastating disease. Viruses and drug-induced hepatotoxicity are the most common causes of the syndrome, but the relevance of each differs depending on the geographic area. In a large proportion of patients no cause for FHF can be identified. Good intensive care is critical for patient survival. Orthotopic liver transplantation (OLT) remains a definitive therapeutic option. Prognostic indices have helped to optimize patient selection and timing for performance of OLT. However, the accuracy of these prognostic indices decreases when they are applied to different populations, probably because of regional differences in etiology and peculiar native host factors. More accurate prognostic criteria and new therapeutic alternatives to OLT are required.