The control of pancreatic secretion at the cellular level probably involves receptor sites that release adenyl cyclase and activate intracellular cyclic AMP. In the case of cells secreting water and electrolyte, there may be activation of an ATPase and active extrusion of sodium as well as bicarbonate or hydrogenion. In the case of enzymes, cyclic AMP also probably plays a ce:role. Control of enzymes is exerted by change in the rate of synthesis and the rate at which the zymogen granules are extruded at the apical cell border. It seems likely that extrusion or secretion occurs first in response to stimulation and that the acinar cells must be depleted of enzymes to a critical level before synthesis accelerates. At least for enzyme secretion, calcium appears to play a ce:role in triggering the intracellular secretory process. In any case, the secretory cells are subjected to control through hormones synthesized or stored in cells of the pyloric and intestinal glands, or both, and the neurohumoral transmitter, acetylcholine. The release of the hormone, gastrin, is under the excitatory influence of local cholinergic reflex arcs and the vagi. The principal inhibitory factor is a low intragastric pH. In the case of the release of intestinal hormones CCK-PZ and secretin, the involvement of the vagi seems clear, but the presence of a local cholinergic mechanism is controversial, and no inhibitory mechanism has been described short of a presumed decrease in hormone-containing cells. Adrenergic influences probably act secondarily to inhibit local cholinergic activity or to decrease blood flow. Acetylcholine seems to have a local stimulating effect on enzyme secretion independent of blood flow, but the response of the pancreas to the sight, smell, and swallowing of food can be explained entirely by the vagal release of gastrin. Another example of interaction is the increased volume and bicarbonate response to secretin in the presence of stimulation that should release CCK-PZ. The recognized extracellular control system therefore consists of the release of secretin and CCK from intestinal mucosal cells in response to the delivery of HCl from the stomach and amino acids as products of digestion in the duodenum and jejunum. Gastrin release in the stomach precedes that of the intestinal hormones and depends upon central nervous stimulation transmitted over the vagi to a local cholinergic and pH sensitive mechanism. The implications of these conclusions in pathophysiology are that hormonal stimulation may fail because: 1) of an inadequate number of hormone-containing cells, i.e., celiac sprue, antrectomy; 2) of a failure of HCl or amino acids to reach the hormone-containing cells, i.e., gastrojejunostomy; and 3) of a reduction in the number of pancreatic secretory cells, i.e., pancreatitis or cancer. In pancreatic function testing, it should be possible to determine the maximal secretory capacity for bicarbonate with secretin and that of enzymes with CCK-PZ. Therapeutic implications include nasogastric suction to prevent the releasers of intestinal hormones from reaching their site of action and to avoid gastric distention, an effective stimulus to gastrin release and reflex cholinergic stimulation. Atropine will reduce cholinergic stimulation and vagotomy impairs release of hormones. There remain many intriguing problems. Does trypsin in the intestinal lumen exert a negative feedback on pancreatic secretion via the blood or impair the release of CCK-PZ? are there several "CCK’s?" What is the signal in adaptation that causes enzyme output to shift toward enzymes appropriate for the substrate? Can the trophic effect of CCK-PZ or gastrin be put to therapeutic use? Will glucagon be useful as a physiologic inhibitor of pancreatic secretion? What is the mechanism of bile salts in stimulating trypsin secretion? Can the induction effect of phenobarbital on growth and enzyme secretion be used therapeutically? These and many other questions indicate a busy and exciting future for students of neurohumoral control of the pancreas.