The human appetite system contains central and peripheral mechanisms that interact with environmental features, especially with the physical and nutrient composition of the food supply. Foods varying in nutrient composition exert different physiologic effects, some of which function as satiety signals. High-fat diets (low food quotient) lead to high levels of energy intake. This effect is termed passive overconsumption and overcomes fat-induced physiological satiety signals. High-fat foods exert a weak effect on satiation (intra-meal satiety), and fat has a weaker effect, joule for joule, on postingestive satiety than do other macronutrients. The frequency of obesity is greater among high-fat than low-fat consumers. However, the development of obesity on a high-fat diet is not a biological inevitability. The investigation of people who resist the weight-inducing properties of high-fat diets is a key research strategy. Understanding the appetite control system suggests behavioral, nutritional, and pharmacologic strategies for modifying dietary fat intake.