Obesity (body mass index, BMI >30) afflicts millions of people in the United States (an estimated 97 million adults in the U.S.) and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke, hypertension, and morbidity. In industrialized countries, the problem of obesity is compounded by overeating, a high fat content diet, and a lack of exercise. The last few years have seen the characterization of over 30 neuroendocrine pathways that have been identified to participate in and regulate feeding behavior and energy homeostasis. The melanocortin pathway includes five genetic factors that have been demonstrated to mediate weight homeostasis, and when modified, result in obesity. The melanocortin pathway includes the melanocortin agonists, derived from the proopiomelanocortin (POMC) gene, the five G- protein coupled (GPCR) melanocortin receptors identified to date (MC1R-MC5R), and the only two naturally occurring antagonists of GPCRs, agouti (ASP) and agouti-related protein (AGRP) identified to date. The five melanocortin genetic factors that have been identified as being involved in energy homeostasis are the POMC, ASP, AGRP, the brain melanocortin-4 receptor (MC4R), and the melanocortin-3 receptor (MC3R) proteins. These data support the hypothesis that the melanocortin pathway is involved in the regulation of energy homeostasis. The objectives of this research are to develop selective MC3R and MC4R agonists, antagonists, and ligands with mixed receptor pharmacology using peptide and non-peptide combinatorial chemistry libraries and approaches, identify MC3R and MC4R mutations which result in changes in ligand receptor selectivity, identify MC3R mutations which differentiate agonism versus antagonism, and examine MC3R/MC4R selective ligands in vivo using mouse models.