Hepatocytes from different subacinar localizations differ not only in their enzyme equipment, but have also different functions in intermediary metabolism. Gluconeogenesis, amino acid breakdown, urea synthesis and oxidative metabolism occur predominantly periportal, whereas glycolysis, glutamine synthesis and drug metabolism are predominantly perivenous. This metabolic zonation is rather dynamic and is influenced by hormones, oxygen-tension, substrate concentrations, circadian rhythms and development. There are metabolic interactions between differently localized hepatocyte populations: the product of one population may serve as the substrate for another. Hepatocyte heterogeneity in ammonia and glutamine metabolism provides new aspects on the pathogenesis of hyperammonemia in severe liver disease. Glutamine is degraded in the periportal area of the acinus, whereas there is a simultaneous resynthesis of glutamine in the perivenous area, resulting in an intercellular glutamine cycle. This provides an effective means for almost complete detoxication of ammonia by urea synthesis. The rate of hepatic bicarbonate elimination is regulated by the intercellular glutamine cycle pointing to the important role of the liver in maintaining pH homeostasis. Such a device also explains the development of an alkalosis in severe liver disease as a consequence of a diminished bicarbonate removal by the liver.