The care of patients with acute liver failure (ALF) presents unique clinical challenges to the practicing physician. It combines the management of rapidly progressive, severe multiple organ failure, unpredictable and often devastating complications, and a need for urgent decision-making in the application of emergency liver transplantation. However, outcomes for patients with this condition have shown progressive improvement over the last four decades. In this article, practical clinical approaches to the care of critically ill patients with ALF are discussed, taking an organ systems-based perspective and discussing the underlying pathophysiological processes and major areas of uncertainty as to what constitutes best practice.