Chronic hepatic encephalopathy (HE) or, preferably at least in the experimental situation, portal-systemic encephalopathy is a neuro-psychiatric syndrome which is frequently observed to accompany patients with hepatic failure. Despite immense research efforts over the years to clarify the pathogenic mechanisms involved, the more precise reasons for the development of HE are still mainly unknown. Several hypotheses have been suggested to explain the development of HE, but so far none of them has been proven unequivocally valid. One such hypothesis today concerns a perturbation of the metabolism of the aromatic amino acid L-tryptophan (L-TRP) in the brain associated with PSE. In a series of ongoing investigations, the possible involvement of L-TRP and L-TRP derived compounds in the development of HE has recently been studied. In the present survey, after a brief introduction of HE neurotransmission failure in general in HE will shortly be discussed. This will be followed by a description focusing on L-TRP-related pathology in the brain in experimental HE. Within this paragraph, a suggested role for the L-TRP-derived neurotox quinolinic acid in the pathogenesis of HE will be discussed. The main part of the present overview will, however, deal with the possible involvement of disturbances in the brain serotonin release associated with HE, including also two other neuroactive L-TRP-related compounds, the serotonin-derived hormone melatonin and the L-TRP derived trace amine tryptamine. After this main section, the hazards involved in an uncontrolled and extensive clinical use of new and potent CNS-active drugs, such as the selective serotonin reuptake inhibitors, in patients suffering from liver failure with overt or pending HE will be discussed. This review will sum up with a short discussion centered around future aspects on relevant strategies to pursue in this field of research.