There is an obesity epidemic in the industrialized world that is not simply explained by excess energy intake and decreased energy expenditure. Persistent obesity develops when genetically predisposed individuals are in a chronic state of positive energy balance. Once established, the obese body weight is avidly defended against both over- and underfeeding. Animal studies have shown that lean individuals who are genetically predisposed toward obesity have abnormalities of neural function that prime them to become obese when caloric density of the diet is raised. These neural abnormalities are gradually "corrected" as obesity becomes fully developed, suggesting that obesity is the normal state for such individuals. Thus, defense of the obese body weight may be perpetuated by the formation of new neural circuits involved in energy-homeostasis pathways that are not then easily abolished. Such neural plasticity can occur in both adult life and during nervous-system development. Early pre- and postnatal metabolic conditions (maternal diabetes, obesity, undernutrition) can lead genetically predisposed offspring to become even more obese as adults. This enhanced obesity is associated with altered brain neural circuitry, and these changes can then be passed on to subsequent generations in a feed-forward cycle of ever-increasing body weight. Thus, the metabolic perturbations associated with obesity during both brain development and adult life can produce "metabolic imprinting" on genetically predisposed neural circuits involved in energy homeostasis. Drugs that reduce body weight decrease the defended body weight and alter neural pathways involved in energy homeostasis but have no permanent effect on body weight or neural function in most individuals. Thus, early intervention in mothers, infants, children, and adults may be the only way to prevent the formation of permanent neural connections that promote and perpetuate obesity in genetically predisposed individuals.