The perinatal environment exerts profound effects on the structure and function of the mammalian central nervous system. This chapter reviews the wide scope of structural and molecular changes that have been observed in specific brain regions involved in appetite regulation, in particular the hypothalamus, when individuals are exposed to an obesogenic environment during perinatal life. Epidemiological and clinical studies have provided valuable information on the role played by maternal obesity and early postnatal over nutrition in increasing the susceptibility for the development of diseases in adult life, including obesity and diabetes. Animal models have also been useful in identifying organizational and regulatory changes that occur within key systems that are involved in metabolic regulation. They showed that exposure to an obesogenic environment during critical periods of life has lasting effects on the development and organization of hypothalamic circuits that regulate body weight and energy balance.