Over the past 35 years, the outlook for a patient presenting with acute liver failure (ALF) has changed beyond all recognition. A patient presenting in 1984 had an 80 % likelihood of succumbing to intracranial hypertension. Today due to dramatic improvements in intensive care in dedicated liver transplant units, this has been reduced to just 20 %. Prompt fluid resuscitation, empirical treatment for sepsis and standardised management protocols that include early intubation and high flow hemofiltration for ammonia removal, limit the numbers of patients who die from the sequelae of cerebral edema and ALF. With the evolution and development of bedside prognostic markers that will include personalised genomic, metabonomic and immune profiling, rationalisation of grafts to those who are not predicted to survive is likely to further minimise the number of grafts utilised. Furthermore, in those patients with a dismal prognosis, the use of plasmapheresis, immunomodulatory therapies, biological liver support systems and hepatocyte transplantation offer a potential bridge until the injured liver can begin to regenerate avoiding transplantation and life-long immunosuppressant therapy.