We summarize the discovery of luminal feedback regulation of pancreatic secretion in rats and its history. In rats, removal of proteolytic activity from the intestine produced a significant increase in pancreatic protein (enzyme) output. This increase was confirmed to be mediated by circulating chole-cystokinin (CCK). Subsequently, two CCK-releasing peptides, monitor peptide and luminal CCK-releasing factor (LCRF), were purified from the rat pancreatic juice and small intestine, respectively, to elicit CCK release in luminal feedback regulation. Furthermore, we emphasize the important physiologic roles of CCK and CCK receptors by the discovery of disrupted CCK-A-receptor gene in rats. These findings should help to determine the regulation of pancreatic secretion and CCK functions in humans.