The melanocortins (MC) are released from neurons and paracrine cells in the CNS where they are involved in important physiological functions, including regulation of body temperature and immune responses. MC bind to melanocortin receptors, a class of cell surface G-protein-coupled receptors. Of the five subtypes of MC receptors that have been cloned in mammals, the MC1, MC3, MC4 and MC5 receptors are expressed in brain tissues. Expression of MC receptors in both brain cells and cells of the immune system suggests direct involvement of MC in regulation of inflammatory processes in the brain. The binding of MC to MC receptors induces activation of adenylate cyclase, increase in intracellular cAMP level and, consequently, inhibition of the nuclear transcription factor kappaB (NF-κB) signalling. Inflammatory processes contribute to development of severe CNS diseases, both in acute and chronic conditions. Thus far, the anti-inflammatory effects of MC in the CNS have been mainly studied using peptides that are relatively unselective for individual MC receptor subtypes. Consequently, these studies do not allow identification of specific MC receptor(s) involved in the regulation of inflammatory processes. However, recently synthesized ligands selective for individual MC receptors indicated that both MC4 and MC3 agonists are promising anti-inflammatory agents in treatment of brain inflammation.