Recent experimental studies in animals and humans provide strong evidence that cholecystokinin (CCK) acts via cholinergic pathways to mediate pancreatic enzyme secretion. These studies indicate that the sites of CCK's action to stimulate pancreatic secretion are dose dependent. Doses of CCK that produce physiological plasma CCK levels act via stimulation of the vagal afferent pathway originating from the gastroduodenal mucosa, whereas doses that produce supraphysiological CCK levels act to stimulate intrapancreatic neurons and pancreatic acini. These CCK-sensitive fibers are also responsive to a wide range of chemical and osmotic stimuli. In this manner, gastrointestinal afferents responding to hormones such as CCK and the ever-changing chemical and physical luminal environment provide sensory information to the central nervous system, which in turn stimulates pancreatic secretion via a vagal cholinergic pathway.