Drug-induced liver injury (DILI) is the most common cause of acute liver failure (ALF) in Western countries. Without liver transplantation, the mortality rate for ALF approaches greater than 80%. Acetaminophen-related ALF may be associated with a rapid progression but fortunately has a high chance for spontaneous survival compared with idiosyncratic DILI-related ALF. Several prognostic scoring systems for severe DILI have been developed to aid clinicians in selecting patients who require urgent liver transplantation. Patients who undergo liver transplantation for ALF are at risk for early graft loss and death and should be closely followed.