Acute liver failure is a rare, life-threatening clinical syndrome marked by the sudden loss of hepatic function in a patient with no prior history of liver disease. Although emergency liver transplantation is often the only life-saving therapeutic option, children correctly diagnosed with well-characterized causes of pediatric acute liver failure may benefit from the early implementation of directed medical therapies. Vigilant intensive and supportive care is critical with specific attention to the development of a myriad of potential complications. The goal of this article is to enable the early recognition of the child presenting in acute liver failure and provide a focused approach to the interim diagnostic and management strategies leading to the timely referral to a pediatric liver transplant center.