Recent experimental studies in animals and humans provide strong evidence that cholecystokinin acts via cholinergic pathways to mediate pancreatic secretion of enzymes and bicarbonate. These findings revolutionize our current concept of the mechanism of action of cholecystokinin on pancreatic exocrine secretion. In addition, it also appears that depending on the stimulants, the release of cholecystokinin from cholecystokinin cells in the upper intestinal mucosa may be modulated by cholinergic input. Studies in rats examined the role of intraluminal proteases and bile acid in the release of cholecystokinin. Physiologic concentrations of bile acid inhibit cholecystokinin release by maintaining luminal trypsin activities, whereas higher concentrations of bile acid inhibit cholecystokinin secretion independent of luminal protease activities. This further illuminates the mechanism responsible for feedback regulation of pancreatic secretion. Human studies support that both somatostatin and the adrenergic pathway modulate interdigestive pancreatic enzyme secretion, indicating complex neural and hormonal mediation of basal pancreatic secretion. A number of new peptides have been reported to modulate pancreatic secretion and growth, and their mechanisms of action were examined and discussed. This suggests that the exocrine pancreas is under complex neurohormonal control.