Clinical progress in the development of new diagnostic modalities and therapeutic strategies for the management of patients with hepatic encephalopathy has lagged behind the vast knowledge that has been generated from basic studies. In this article, we critically assess matters that should be revisited, such as definition, classification, diagnosis and grading of hepatic encephalopathy, which are difficult to apply reproducibly using the current criteria. Many lines of investigation have confirmed that hepatic encephalopathy is irreversible in many patients and suggest the need for further studies focussing on mechanisms of neuronal injury and death, to guide future drug development for these patients. The clinical evidence behind using lactulose for all severities of hepatic encephalopathy, which is currently considered the standard of care, is poor and placebo-controlled trials for hepatic encephalopathy should be considered ethically sound. This expert opinion identifies current challenges in hepatic encephalopathy and highlights areas which require further debate and investigation in order to help advance the field both scientifically and clinically.