Glutamate is the main excitatory neurotransmitter in mammals. Glutamatergic neurotransmission involves several steps, beginning with release of glutamate from the presynaptic neuron. Glutamate in the extracellular space activates glutamate receptors present in the synaptic membranes, leading to activation of signal transduction pathways associated with these receptors. To avoid continuous activation of glutamate receptors, glutamate is removed from the synaptic cleft by specific glutamate transporters located mainly on astrocytes. All these steps are tightly modulated under physiological conditions, and alterations of any of the above steps may result in impairment of glutamatergic neurotransmission, leading to neurological alterations. There are studies in the literature reporting alterations in all these steps in hyperammonemia and/or hepatic failure. Glutamatergic neurotransmission modulates important cerebral processes. Some of these processes are altered in patients with liver disease and hepatic encephalopathy, who show altered sleep-wake patterns, neuromuscular coordination, and decreased intellectual capacity. The alterations in glutamatergic neurotransmission may be responsible for some of these neurological alterations found in hepatic encephalopathy. The effects of hyperammonemia and liver failure on different steps of glutamatergic neurotransmission including alterations of glutamate concentration in the extracellular fluid in brain, transport and transporters of glutamate, the content and function of different types of glutamate receptors and signal transduction pathways. Alterations induced by hyperammonemia and liver failure on the glutamate-nitric oxide-cGMP pathway in brain may result in changes in long-term potetiation and learning ability.