Acute liver failure is present when any type of rapid-onset liver insult results in a common systemic pathophysiologic picture: altered mental status, vasodilation, renal and pulmonary failure, frequent infection, and poor outcome without transplantation. Identifying which of the many different causes is a first step in understanding prognosis and options for treatment. However, identifying the correct cause can be difficult and sometimes impossible. Any discussion of etiologies must take a historical perspective; there have been several evolving trends nationally and internationally over the past three decades. Etiologies also vary worldwide with considerable differences apparent between Western countries and the developing world. In Europe and North America a large proportion of cases are due to acetaminophen and to idiosyncratic drug reactions, whereas reports from emerging countries in Asia and Africa feature viral illnesses, particularly hepatitis B and E. Determining etiology is important for two reasons: specific antidotes or therapies may be indicated once the diagnosis is known, and knowing the cause provides a reasonably valid guide to predicting outcome.