Roux-en-Y bypass surgery is increasingly used for treatment of gross obesity due to the general inability of lifestyle change and existing drug treatments to counter the obesity epidemic. This common form of bariatric surgery involves bypass of the small intestine with significant reduction of body of weight that is independent of malabsorption. Strikingly, obesity-related diabetes is also cured by the procedure but prior to body weight loss. This is due to rapid improvement of insulin resistance and associated pancreatic beta-cell function. Several hypotheses have been proposed to account for this phenomenon, but the most attractive concerns surgical ablation of gastric inhibitory polypetide (GIP)-secreting intestinal K-cells. Thus, circulating GIP levels are decreased after Roux-en-Y bypass surgery and GIP is known to play a key role in lipid metabolism and fat deposition. Further, both genetic and chemical ablation of GIP in animal models has been shown to protect against obesity and associated metabolic disturbances. These observations in animals and man suggest that GIP receptor antagonism may afford an alternative therapeutic option for treatment of obesity-diabetes.