Functional disruption of either MC3R or MC4R results in obesity, implicating both in the control of energy homeostasis. The ligands for these receptors are derived from the prohormone proopiomelancortin (POMC), which is posttranslationally processed to produce a set of melanocortin peptides with a range of activities at the MC3R and MC4R. The relative importance of each of these peptides α-MSH, γ3-MSH, γ2-MSH, γ-lipotropin (γ-LPH) and, in man but not in rodents, β-MSH] in the maintenance of energy homeostasis is, as yet, unclear. To investigate this further, equimolar amounts (2 nmol) of each peptide were centrally administered to freely feeding, corticosterone-supplemented, Pomc null (Pomc^−/−) mice. After a single dose at the onset of the dark cycle, α-MSH had the most potent anorexigenic effect, reducing food intake to 35% of sham-treated animals. β-MSH, γ-LPH, and γ3- and γ2-MSH all reduced food intake but to a lesser degree. The effects of peptide administration over 3 d were also assessed. Only α-MSH significantly reduced body weight, affecting both fat and lean mass. Other peptides had no significant effect on body weight. Pair-feeding of sham-treated mice to those treated with α-MSH resulted in identical changes in total weight, fat and lean mass indicating that the effects of α-MSH were primarily due to reduced food intake rather than increased energy expenditure. Although other melanocortins can reduce food intake in the short-term, only α-MSH can reduce the excess fat and lean mass found in Pomc^−/− mice, mediated largely through an effect on food intake.