Acute liver failure (ALF) is a dramatic, highly unpredictable clinical syndrome defined by the sudden onset of coagulopathy and encephalopathy. Acetaminophen overdose, the leading cause of ALF in the United States, has a 66% chance of recovery with early N-acetylcysteine treatment and supportive care. Cerebral edema and infectious complications are difficult to detect and treat in these patients and may cause irreversible brain damage and multiorgan failure. One-year survival after emergency liver transplantation is 70%, but 20% of listed patients die, highlighting the importance of early referral of patients who have ALF with a poor prognosis to a transplant center.