The signaling of fat mass to central nervous system (CNS) regulators of food intake, energy expenditure and fertility has been inferred by experimental physiologists for over 75 years. The ability to modify such phenotypes based upon the status of body energy stores (fat) has critical survival value and, therefore, has been the object of potent selection pressure in evolution. The recent molecular cloning of the mouse ob mutation and the subsequent elucidation of the fundamentals of its regulatory physiology has identified a protein secreted by adipocytes, leptin, as a plausible candidate for a humoral signal with the requisite endocrinology and neurobiology.