The negative control of pancreatic exocrine secretion in man occurs during the interdigestive and postprandial periods of the digestive cycle. The physiological mechanisms involved include negative feedback mechanisms, well described and accepted in animals, and controlled by the cholecystokinin- and secretin-releasing factors of pancreatic and duodenal origin, along with the active pancreatic proteases present in the upper gut. The presence of these factors and their efficacy in humans, however, have their supporters and detractors, with a possibility for reconciliation among opponents. Besides these releasing factors, hormones, mostly from the intestine, are also involved in this inhibitory process of pancreatic secretion. Somatostatin, peptide YY, pancreatic polypeptide, glucagon, ghrelin, and leptin were described as potentially involved from studies mostly performed on animals. Finally, bile and bile salts have mixed responses on this inhibition, and their effects seem to be at the intestine level with gastrointestinal hormones involved. Future studies will have to be performed in humans to determine the presence of cholecystokinin- and secretin-releasing factors and their role. Finally, the demonstrated modulatory action of hormones and bile acids in other species needs to be confirmed in humans.