The stimulation of exocrine pancreatic secretion has extensively been studied in the past. On the other hand, little is known about the factors and mechanisms which regulate inhibition of exocrine pancreatic secretion. This review, therefore, focuses on somatostatin as one candidate of several peptides which may physiologically mediate inhibition of pancreatic secretion and on its possible mode of action. Somatostatin probably inhibits pancreatic exocrine secretion by a variety of mechanisms which depend on the species and the type of secretion studied (postprandial vs. interdigestive secretion, protein vs. bicarbonate secretion): Somatostatin may act via inhibition of the release of circulating hormones such as cholecystokinin (CCK) and secretin or via intrapancreatic inhibition of the release or action of CCK. Somatostatin may inhibit acetylcholine release from nerve terminals which express specific somatostatin receptors or directly affect the secretory response of the acinar cells via specific somatostatin receptors by a reduction of intracellular cAMP. Somatostatin may also indirectly alter the pancreatic response to a meal by its extrapancreatic effects, e.g. inhibition of gastric secretion, gastric emptying, gallbladder emptying and gastrointestinal motility.