The belief that the hypothalamus plays a role in the regulation of energy homeostasis was originally based upon the results of brain lesions. Disruption of the ventromedial hypothalamus produced hyperphagic obesity, while lesions of the lateral hypothalamus caused hypophagia and weight loss, suggesting the existence of ventromedial “satiety” and lateral “feeding” centers. Although this framework is now recognized as simplistic, it is the scaffold upon which an understanding of the complex neurochemical system underlying regulation of appetite and energy expenditure has been built. Initially, physiologists examined the responses to injection of neurochemicals present in and around the hypothalamus, using feeding, autonomic output, and hormonal measurements as a final readout. Such approaches defined the effects of the neurotransmitters norepinephrine, dopamine, and serotonin, as well as neuropeptides including neuropeptide Y (NPY), corticotropin-releasing hormone (CRH), and galanin; and elements of a neural wiring diagram began to take shape. Indeed, it appeared possible, until several years ago, that the key molecular mediators in the brain were known, and only their mode of interaction remained to be defined. But the stability of body weight in the face of variable nutritional supplies suggested that additional molecular mediators and regulatory pathways remained undiscovered. This suspicion has been validated by a number of recent discoveries, including one in this issue of Cell (