The intent of this review is to provide a broad overview of the interorgan metabolism of glutamine and to discuss in more detail its role in acid-base balance. Muscle, adipose tissue, and the lungs are the primary sites of glutamine synthesis and release. During normal acid-base balance, the small intestine and the liver are the major sites of glutamine utilization. The periportal hepatocytes catabolize glutamine and convert ammonium and bicarbonate ions to urea. In contrast, the perivenous hepatocytes are capable of synthesizing glutamine. During metabolic acidosis, the kidney becomes the major site of glutamine extraction and catabolism. This process generates ammonium ions that are excreted in the urine to facilitate the excretion of acids and bicarbonate ions that are transported to the blood to partially compensate the acidosis. The increased renal extraction of glutamine is balanced by an increased release from muscle and liver and by a decreased utilization in the intestine. During chronic acidosis, this adaptation is sustained, in part, by increased renal expression of genes that encode various transport proteins and key enzymes of glutamine metabolism. The increased levels of phosphoenolpyruvate carboxykinase result from increased transcription, while the increase in glutaminase and glutamate dehydrogenase activities result from stabilization of their respective mRNAs. Where feasible, this review draws upon data obtained from studies in humans. Studies conducted in model animals are discussed where available data from humans is either lacking or not firmly established. Because there are quantitative differences in tissue utilization and synthesis of glutamine in different mammals, the review will focus more on common principles than on quantification.Keywords: Glutamine, metabolic acidosis, glutaminase, glutamine synthetase, phosphoenolpyruvate carboxykinase.The structure and function of proteins and of macromolecular complexes are critically dependent upon the hydrogen ion concentration of the surrounding medium. As a result, higher eukaryotes maintain the pH of the extracellular fluid and of various intracellular compartments within narrow limits. For example in humans, normal arterial plasma pH is 7.40 Ϯ 0.05. Fluctuations in excess of 0.5 pH units from this value are usually lethal. Thus, the maintenance of normal acid-base balance is essential for survival. The major acid generated as a byproduct of catabolism is CO 2 . A normal individual generates ϳ20 mol of CO 2 per day. However, this acid is volatile and is readily expelled by the lungs. The relative concentrations of HCO 3 Ϫ and CO 2 are the primary determinants of plasma pH. The HCO 3 Ϫ / CO 2 system has a pK of 6.1 and would appear to be a relatively ineffective buffer at pH 7.4. This system is made effective by the ability to maintain a constant CO 2 concentration through changes in the rate of respiration. Various diseases of the lung or disorders of the central nervous system can result in either hypo-or hyperventilation [1]. The former c...