Acute liver failure (ALF) is a rare dynamic condition in which rapid deterioration of liver function results in altered mentation and coagulopathy in individuals without known preexisting liver disease. Hyperacute (onset of encephalopathy 0–7 days), acute (onset of encephalopathy 7–28 days) and subacute (onset of encephalopathy > 28 days) are the classifications of the ALF. Viral Infections and drug-induced Injury are the causes of the ALF. Liver transplantation is emerged as the only therapeutic option with proven benefit in advanced ALF. Rapid evaluation for transfer to a transplantation center and consideration for liver transplantation is mandatory so that transplantation can be applied before contraindications develop. Substance abuse, suicidal predilection, psychiatric disorders, uncontrollable sepsis and other organ system involvement must be excluded in contraindications to transplantation. Pathogenesis of acute liver failure, clinical management, intracranial hypertension, role of ICP monitoring, management of coagulopathy, management of hemodynamics, renal failure management, infectious disease considerations, liver support devices are also covered in this chapter.