Acute liver failure (ALF) is a syndrome of diverse etiology, in which patients without previously recognized liver disease sustain a liver injury that results in rapid loss of hepatic function. Depending on the etiology and severity of the insult, some patients undergo rapid hepatic regeneration and spontaneously recover. However, nearly 60% of patients with ALF in the US require and undergo orthotopic liver transplantation or die. Management decisions made by clinicians who initially assess individuals with ALF can drastically affect these patients' outcomes. Even with optimal early management, however, many patients with ALF develop a cascade of complications often presaged by the systemic inflammatory response syndrome, which involves failure of nearly every organ system. We highlight advances in the intensive care management of patients with ALF that have contributed to a marked improvement in their overall survival over the past 20 years. These advances include therapies that limit the extent of liver injury and maximize the likelihood of spontaneous recovery and approaches to enable prevention, recognition and early treatment of complications that lead to multi-organ-system failure, the most common cause of death. Finally, we summarize the role of orthotopic liver transplantation in salvage of the most severely affected patients.