The central melanocortin circuitry is at the heart of the adipostat, and functions as a bidirectional switch on the control of energy storage. The circuitry is composed of the anorexigenic arcuate POMC neurons, and the orexigenic arcuate AgRP neurons, and their melanocortin-3 (MC3R) and melanocortin-4 (MC4R) target neurons, found in key neuroendocrine, behavioral, and autonomic control sites throughout the brain. Mutations in the MC4R, present at a composite allele frequency as high as 1 in 1500, are the most common cause of human syndromic obesity. The MC4R is a well validated target for the treatment of syndromic obesity, but a lack of understanding of the structure and function of the receptor have hindered the development of MC4R agonists for the treatment of common dietary obesity. New data on the molecular structure and signaling of the MC4R will be presented here that may aid in the development of next generation MC4R therapeutics. Understanding of the role of the MC3R has been slower to develop. Recently, we demonstrated that the MC3R is expressed presynaptically on AgRP neurons, regulates GABA release from these cells, and is required for control of the boundary conditions of energy homeostasis. We now demonstrate the mechanistic utility of stimulation or inhibition of MC3R neurons using both genetic and pharmacological tools.