Cholecystokinin (CCK) is a member of a family of gastrointestinal peptides known to physiologically regulate pancreatic protein secretion, gallbladder contractility, and gut motility. In addition, CCK has been found to play important roles in endocrine and neural systems in the periphery as well as in the central nervous system. CCK has been proposed to play a role in satiety, anxiety, and intestinal transit in addition to its well-described effects in coordinating digestion of a meal. We and others have shown that exogenous and endogenous CCK prevent gastric injury from luminal irritants. These data suggest that the release of CCK may represent an important component of the intrinsic gastric mucosal defense system. This review focuses on the ability of CCK to render the stomach more resistant to injury from luminal insults and will summarize recent studies that examine the possible mechanisms involved.