Acetaminophen and idiosyncratic drug induced hepatotoxicity are the most commonly identified etiologies of acute liver failure in Western countries. Infectious complications and cerebral edema remain the leading causes of death. Moderate hypothermia and other medical interventions may improve cerebral edema in selected patients with acute liver failure. In addition, pilot studies suggest that recombinant factor VIIa infusions may allow for the safe placement of intracranial pressure monitoring devices in patients with cerebral edema and severe coagulopathy. Auxiliary liver transplantation and bioartificial liver devices offer the hope of temporary liver support for selected patients with a high likelihood of native liver regeneration. Prognostic survival models that include arterial lactate levels may improve our ability to identify acetaminophen overdose patients in urgent need of liver transplantation. The lower 1-year patient survival following liver transplantation for acute liver failure compared to chronic liver failure (60 vs 80%) is in part due to the emergent nature of surgery, concomitant vital organ failure, and the higher incidence of immunologically mediated graft dysfunction. Vaccination against hepatotrophic viruses and other public health measures designed to minimize the incidence of both intentional and non-intentional acetaminophen overdose may help reduce the future incidence of acute liver failure. In the meanwhile, it is recommended that acute liver failure patients be managed in experienced centers with ready access to liver transplantation to optimize outcomes in this rare but frequently fatal illness.