Cocaine- and amphetamine-regulated transcript (CART) codes for a neuropeptide system with a number of biological roles. The high conservation of CART across species suggests that it has an important role in mammalian physiology. CART is widely expressed in the central nervous system and the periphery, but is particularly concentrated in the hypothalamus. CART peptides, particularly CART (55-102), appear to have an important function in the regulation of energy homeostasis. This review aims to dissect the role of CART in appetite and energy expenditure. CART interacts with a number of central appetite circuits. Hypothalamic CART expression is regulated by a number of peripheral factors, including the adipose hormone leptin. Intracerebroventricular administration of CART (55-102) reduces appetite and stimulates energy expenditure. Hypothalamic CART may also play an orexigenic role under specific circumstances, however, as injection of CART (55-102) into specific hypothalamic nuclei increases food intake.