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Ammonia is a neurotoxin that is implicated in the pathogenesis of hepatic encephalopathy due to acute and chronic liver failure. However, its relation to neurological damage and brain edema is poorly understood. During the last decades, it has been the prevailing hypothesis that an osmotic disturbance induced by the astrocytic accumulation of glutamine leads to brain edema. However, various findings are at variance with this hypothesis. The present review will discuss: (a) correlation of ammonia with encephalopathy and brain edema in HE; (b) glutamine synthesis and astrocyte swelling; (c) glutamine synthesis and the glutamine-cycle: relation to brain energy metabolism; (d) glutamine synthesis and the glutamate–glutamine cycle and its relation to anaplerotic activity; (e) evidence favouring the “glutamine hypothesis”; (f) evidence contradicting the “glutamine hypothesis”; (g) glutamine synthesis and osmoregulation; (h) glutamine synthesis in chronic liver failure; (i) impaired brain energy metabolism in acute liver failure (ALF) and its relation to astrocytic glutamine synthesis. Taken together, the precise role of glutamine in the development of brain edema in ALF remains unclear. Astrocytic changes due to glutamine accumulation may lead secondarily to effects on brain energy metabolism. However, the relation between impaired energy metabolism and glutamine accumulation has not been well established. It is noteworthy that no single biochemical factor appears to be responsible for the many symptoms of HE. For example, brain glutamine accumulation and low-grade brain edema occur in chronic liver failure (CLF) suggesting common mechanisms are responsible for the neurological dysfunction in CLF and ALF. Recent NMR spectroscopic studies have provided considerably new information in this area. Future NMR studies using the stable isotope 13C may be useful in the study of the dynamics of brain metabolism in patients with ALF so as to better elucidate the precise role of glutamine accumulation and of glutamine-independent components to brain edema in ALF.