In this review to the authors provide evidence-based definitions of organ failure in patients with acute decompensation of cirrhosis, describe the prevalence and prognostic impact of organ failure in these patients, and highlight current knowledge of the mechanisms responsible for its development. Excessive inflammatory response and a reduction of the capacity of organs to respond adequately to stress may sensitize cirrhotic patients to inflammation-driven organ damage and failure. The dynamic evolution of organ failure during early intensive management may provide a useful tool for guiding subsequent management strategies, or in some cases, for defining the futility of care. Currently, management of patients with acute-on-chronic liver failure is mainly supportive. Understanding the mechanisms of immunopathology and failed organ tolerance in acute decompensated cirrhosis could open new areas of research and define new therapeutic options in this life-threatening condition.