Acute-on-chronic liver failure (ACLF) is an emerging clinical syndrome in patients with underlying liver disease that is usually triggered by one or multiple insults and characterized by progressive hepatic and nonhepatic organ failure, a significant risk of infections, and high short-term mortality rates. Despite our incomplete understanding of the underlying pathophysiology, ACLF requires timely diagnostic and therapeutic measures aiming at the identification and elimination of causative factors as well as the prevention of complications to improve the prognosis of affected patients.