In humans, mice, and other mammals, the melanocortin system consists of four peptide hormones with a core amino acid sequence of histidine- phenylalanine-arginine-tryptophan and five melanocortin receptors. Both the melanocortin hormones and their receptors are produced in diverse tissues throughout the body. The ligand of primary interest for treatment of insulin resistance is α-melanocyte-stimulating hormone (α-MSH), which is derived, as are all melanocortins, from tissue-specific post-translational proteolytic processing of the proopiomelanocortin (POMC) precursor protein. Recent results have shown that α-MSH is the complement of leptin in the endocrine circuit, regulating bodyweight, food intake, and metabolic rate. α-MSH can decrease bodyweight, weight gain, and food intake in mice with diet-induced and genetic obesity. As obesity is a major risk factor for type 2 diabetes mellitus, it was reasonable to investigate the endocrine agents involved in obesity for their involvement in diabetes. α-MSH analogs have also been shown to affect blood glucose levels in some mouse models of obesity. For instance, the POMC null mouse is extremely sensitive to insulin in an insulin tolerance test, while being otherwise euglycemic. The results from rodent studies with α-MSH suggest reciprocal effects: α-MSH appears to increase sensitivity to insulin when present in the CNS, while α-MSH in the periphery is necessary for insulin resistance. Should these trends be validated in humans, α-MSH-based therapeutics specifically active in the CNS or peripheral circulation may be promising for the treatment of type 2 diabetes.