Clearly, obesity and its related disorders have become a serious national health concern. Despite the increasing number of Americans with obesity, the pathophysiological basis for aberrant feeding behavior and body weight regulation is not well understood. It is now established that melanocortin 4 receptors (MC4-Rs) are critical regulators of body weight homeostasis in rodents and humans. However, the specific populations of neurons that mediate these effects are still largely unknown. It is our hope to identify critical sites expressing MC4-Rs in the CNS that underlie the anti-obesity properties of MC4-R agonists. In addition to the established role of the central melanocortin system in regulating food intake, several studies suggest that melanocortinergic circuits also regulate insulin action. Thus, identifying the MC4-R circuits in the CNS that are required for normal body weight homeostasis will provide therapeutic opportunities for both obesity and type II diabetes.