Stability of body composition requires that energy intake equals energy expenditure when integrated over prolonged periods. As recent human studies have failed to demonstrate active changes in energy expenditure with changes in body composition, it is likely that energy intake is continually adjusted to preserve a constant total adipose tissue mass. If adipose tissue mass is regulated directly, then there must be some input reflecting this quantity to the central nervous system for the purpose of making corrective changes in appetite when total body fat content fluctuates. The nature of this input has been examined in a variety of animal experiments involving induced weight change, lipectomy, plasma transfer from obese or satiated animals to hungry animals, and parabiosis between obese and lean animals. The bulk of evidence suggests that the plasma level of one or more currently unidentified stable circulating molecules increases in proportion to total body fat content and augments the effect of meal-related satiety signals in the central nervous system. The implications of this adipose tissue-related satiety factor for the pathogenesis of obesity, and the possible nature of the factor are discussed.