Acute liver failure (ALF) is a critical illness whose study and treatment is complicated by its rarity, severity and phenotypic heterogeneity. For many years the cause of ALF has been recognised as a key determinant of its principal clinical manifestations and the course that a patient will follow. Different etiologies are recognised as prognostically ‘favourable’ or ‘unfavourable’ and integrated into systems used to predict outcome with medical supportive care alone, and to identify candidates for liver transplantation (LT) . These differences are illustrated by the variation of different forms of drug-induced ALF. Patients with illness from ‘unfavorable’ idiosyncratic drug-induced liver injury (DILI) often have slow onset of illness and evolution of encephalopathy, only moderate coagulopathy but marked jaundice and often a very poor survival with medical supportive care alone. By contrast, those with ‘favourable’ acetaminophen (APAP) induced ALF, usually occurring after overdose, have illness typically characterised by very rapid onset of disease, minimal jaundice but major coagulopathy, severe multi-organ failure and encephalopathy with – at least historically – the development of cerebral edema (CE) and intra-cranial hypertension (ICH). Despite this severity of illness, recovery with medical care alone is much more likely than in unfavourable etiologies.This article is protected by copyright. All rights reserved.