Food intake and energy expenditure are determinants of metabolic phenotype and are regulated by the CNS. Although humans have a well-balanced homeostatic feedback loop, obesity and metabolic disorders are spreading rapidly and carry a heavy toll of morbidity and mortality. The past decade has witnessed major advances in the understanding of basic metabolic processes, the brain circuitry that determines appropriate and, but, inappropriate behavioral and humoral responses to changing metabolic cues remains largely ill defined. This review summarizes current knowledge of the brain anatomy that supports food intake and energy expenditure and discusses cellular mechanisms such as synaptic plasticity that may provide clues toward the development of successful central therapies to combat metabolic disorders, including obesity and diabetes.