SummaryThe many early hypotheses put forward to account for the production of hydrochloric acid by the stomach were based on electro‐, inorganic or organic chemistry. They are discussed and shown to be incorrect or incomplete. The site of hydrochloric production is the pericanalicular zone round the intracellular canaliculi of the oxyntic cells.Hydrochloric acid secretion in the intact animal and by isolated gastric mucosa can be stimulated by histamine; there is a concomitant rise in the rate of respiration. For every hydrogen ion secreted by the oxyntic cells there is an uptake of one molecule of carbon dioxide, and one bicarbonate ion is formed and exchanged for a chloride ion from the sodium chloride of the bloodin vivo, or of the saline solutionin vitro.The consequent increase in the sodium bicarbonate content of the blood leads to the ‘alkaline tide’ of the urine following acid secretion, and the hydration of carbon dioxide to form these bicarbonate ions is so rapid that carbonic anhydrase activity is required within oxyntic cells. The amount of this enzyme found in oxyntic cells is easily able to produce the required extra uptake of carbon dioxide. Virtually complete inhibition of carbonic anhydrase in isolated gastric mucosa leads to inhibition of acid secretion and damage to the cells indistinguishable from that occurring when acid secretion is stimulated by histamine in the absence of external supplies of carbon dioxide. A similar inhibition of carbonic anhydrase in the intact animal would lead to its speedy death by interference with carbon dioxide transport in the blood.The actively acid‐secreting stomach requires supplies of carbon dioxide from the arterial blood and has a negative respiratory quotient. There is an overall uptake of oxygen and carbon dioxide. The rate of acid secretion is so high relative to the oxygen uptake that the hydrogen ions cannot arise from, or be produced at the same rate as, acids such as pyruvic or carbonic formed during the normal course of oxidative metabolism with the oxyntic cells.The initial source of the hydrogen ions of the gastric juice must be largely or entirely the hydrogen atoms of water.There is a natural, maintained potential difference (p.d.) across gastric mucosa, the secretory surface being negative in an external circuit to the nutrient surface. When the two sides of the mucosa are connected electrically a continuous current can be maintained representing up to about 10% of the metabolic energy. The natural potential decreases with the onset of acid secretion. The rate of acid secretion can be increased or decreased by passing electric current from a battery through the mucosa so as to increase or decrease the p.d. across the tissue.Experiments with a variety of metabolic inhibitors show that the whole of the main pathways of aerobic respiration, fermentation and the related phosphorylations are apparently required to maintain the p.d. and acid secretion.The very high rates of acid secretion in mammalian oxyntic cells and the rates of secretion relative to the oxygen uptakes in amphibian oxyntic cells show that the thermodynamic efficiency of the process is remarkably high.The available evidence shows that two related mechanisms of acid secretion are possible. In mechanism i, the metabolic hydrogen atoms from glucose and water, which are transported by the dehydrogenases, become oxidized to hydrogen ions at the cytochrome level, and the electrons react with oxygen and water to form first hydroxyl ions, and then bicarbonate ions by further reactions with carbon dioxide. This process uses the redox energy from the level of atmospheric oxygen to that of the cytochromes.In mechanism 2, phosphate bond energy, generated by reactions at lower redox levels, is utilized to concentrate hydrogen ions, formed by ionization from water, in an electron‐cycle mechanism in which hydrogen ions are reduced to covalent hydrogen atoms, transported by a carrier system and oxidized to hydrogen ions at high concentration as a result of a coupled phosphorylation. Kinetic and thermodynamic considerations show that the hydrogen carrier and electron transport systems could be oxaloacetate‐malate and cytochromebor perhaps fumarate‐succinate and cytochromec.Both mechanisms require a spatial array of enzymes in the pericanalicular zone of the oxyntic cells, and in both cases chloride ions move in the opposite direction to, and as a result of, the movement of the electrons carried by the cytochromes.The rate of transport of water by the oxyntic cells is so enormous that it could not be handled molecule by molecule by any known enzyme systems. The water must be moved in bulk, and probably flows osmotically as a result of the secretion of the hydrogen and chloride ions by the