Mutations reducing the functional activity of leptin 1, 2, the leptin receptor 3, 4, α–melanocyte stimulating hormone 5 (α–MSH) and the melanocortin–4 receptor 6 (Mc4r) all lead to obesity in mammals. Moreover, mutant mice that ectopically express either agouti 7 (A y/a mice) or agouti–related protein 8 (Agrp), antagonists of melanocortin signalling 8, 9, become obese. These data suggest that α–MSH signalling transduced by Mc4r tonically inhibits feeding; however, it is not known to what extent this pathway mediates leptin signalling. We show here that Mc4r–deficient (Mc4r–/–) mice do not respond to the anorectic actions of MTII, an MSH–like agonist, suggesting that α–MSH inhibits feeding primarily by activating Mc4r. Obese Mc4r–/–mice do not respond significantly to the inhibitory effects of leptin on feeding, whereas non–obese Mc4r–/–mice do. These data demonstrate that melanocortin signalling transduced by Mc4r is not an exclusive target of leptin action and that factors resulting from obesity contribute to leptin resistance. Leptin resistance of obese Mc4r–/–mice does not prevent their response to the anorectic actions of ciliary neurotrophic factor (CNTF), corticotropin releasing factor (CRF), or urocortin; or the orexigenic actions of neuropeptide Y (NPY) or peptide YY (PYY), indicating that these neuromodulators act independently or downstream of Mc4r signalling.