Fat is a vital macronutrient, and its intake is closely monitored by an array of molecular sensors distributed throughout the alimentary canal. In the mouth, dietary fat constituents such as mono- and diunsaturated fatty acids give rise to taste signals that stimulate food intake, in part by enhancing the production of lipid-derived endocannabinoid messengers in the gut. As fat-containing chyme enters the small intestine, it causes the formation of anorexic lipid mediators, such as oleoylethanolamide, which promote satiety. These anatomically and functionally distinct responses may contribute to the homeostatic control and, possibly, the pathological dysregulation of food intake.