Abstract: The antiinflammatory effects of α-melanocyte-stimulating hormone (α-MSH) molecules, specifically α-MSH(1-13) and its COOH-terminal tripeptide α-MSH(11-13), are well established. The peptides have been effective in tests of all major models of inflammation, and more recent tests have been extended to include experimental inflammatory bowel disease, CNS ischemia/reperfusion injury, and bacterial endotoxin-induced inflammation within the brain. The broad effectiveness of α-MSH molecules in all major types of inflammation indicates that the peptides exert actions that are very basic to the inflammatory process. Three general mechanisms of antiinflammatory action of α-MSH molecules have been identified: inhibition of production of inflammatory mediators by, or inhibition of inflammatory actions of, peripheral host cells; inhibition of peripheral inflammation induced by actions on melanocortin receptors within the brain; inhibition of CNS inflammation by local action of the peptides. It appears that α-MSH molecules have multiple actions that modulate the primitive inflammatory response.