This chapter discusses the diagnosis, evaluation and management of fulminant hepatic failure. Patients can present with hypotension due to generalized systemic inflammatory response, coagulopathy, and encephalopathy with progression to coma and brain herniation. Diagnosis is based on clinical presentation and laboratory findings. Critical care management should be performed for cardiovascular, pulmonary, and infectious complications and other comorbidities. Prognosis and treatment decisions can be based on Rumack-Matthew nomogram. Renal failure occurs in up to 50% of cases, even more frequently in acetaminophen toxicity. In most cases continuous renal replacement therapy is indicated. Intermittent hemodialysis should be avoided as some evidence suggests rapid fluid shifts lead to brain herniation. Patients should be transferred to a transplantation facility as soon as possible. If a transplantation center is not readily available, consider transfer to a center that utilizes molecular adsorbents recirculation system (MARS) or artificial extracorporeal liver support therapy.