Of the obesity targets currently being pursued in academia and in industry, rodent and human genetic data and pharmacological results from several rodent obesity models provide a high degree of target validation for the melanocortin-4 receptor (MC4R). MC4R is widely distributed throughout the brain. 1 This distribution pattern correlates with brain sites displaying high sensitivity to melanocortin-regulated feeding behavior. The ligands for MC4R are also expressed in the hypothalamus, within leptin-responsive neurons in the arcuate nucleus where their expression is regulated by alterations in energy balance. Therefore, it is hypothesized that MC4R agonists will cause sustained body weight loss by decreasing food intake without a compensatory reduction in energy expenditure. Hence, there has been an intense effort to identify selective agonists of the MC4 receptor as possible treatments for obesity.