The existence of a biological basis for the regulation of body composition was established by the characterization of rodent models of obesity caused by single gene mutations and experimental hypothalamic lesions (1). Obesity induced by hypothalamic lesions clearly demonstrated the major impact of the central nervous system and the neuroendocrine system in regulating ingestive behavior and energy expenditure. The identiﬁcations of the leptin/leptin receptor and the melanocortin systems by molecular genetics and positional cloning methodologies provided clear molecular and cellular substrates for the interactions between peripheral tissues (adipocytes in the case of leptin, and pancreatic beta cells in the case of insulin) and the brain. Other elements of the neuroendocrine system such as growth hormone, cortisol, thyroid hormone, and sex steroids/gonadotropins inﬂuence the disposition of ingested calories toward expenditure or storage in various tissues as speciﬁc molecules (‘‘partitioning’’). This chapter reviews the insights regarding the control of energy homeostasis that have come from the identiﬁcation and functional characterization of the monogenic mouse obesities and their human orthologs.