The three stimulants of gastric acid secretion likely to have physiological roles in regulation of secretion are acetylcholine, gastrin, and histamine. Acetylcholine is released by vagal and intramucosal reflex stimulation, acting directly on the parietal cell. Gastrin is released by peptides and free amino acids in the stomach and is the only known hormonal stimulant of acid secretion. Release of gastrin by acetylcholine may occur. However, cholinergic control of gastrin release is complex since under certain conditions anticholinergic drugs may actually enhance gastrin release. Factors regulating histamine release have not been defined, but studies with H2-receptor antagonists leave little doubt that histamine has an important role in acid secretion. Studies with isolated parietal cells indicate that histamine, gastrin, and acetylcholine each appear to act at separate receptors on the parietal cell. Anticholinergic agents specifically prevent the cellular actions of acetylcholine, cimetidine specifically inhibits stimulation by histamine, and neither inhibitor blocks the small direct response to gastrin. Furthermore potentiating interactions occur between histamine, gastrin, and cholinergic agents which may account for the interdependence of secretagogue action observed in vivo. Direct potentiating interactions occur between histamine and gastrin and histamine and carbachol but not between carbachol and gastrin. However, in the presence of histamine, carbachol, and gastrin, a three-way potentiation does occur. By interfering with the potentiating interactions between stimulants, anticholinergic agents and cimetidine display an apparent cross-specificity in vitro that resembles the effects of these agents in intact mucosa. The mechanisms underlying these interactions are unknown, but the actions of histamine appear to be mediated through increased production of cyclic AMP and cyclic AMP analogs, which mimic the interactions involving histamine itself. The secondary effectors for acetylcholine and gastrin and the mechanisms for amplification of the response to combinations of stimulants remain to be elucidated.