Proopiomelanocortin (POMC) is a common precursor of melanocortin (MC), the collective term for adrenocorticotropic hormone (ACTH) and melanophore-stimulating hormone (MSH), and of beta-endorphin (beta-END). Over the past decade, considerable progress has been made in the analysis of the POMC gene from a board taxonomic group of vertebrates and invertebrates. The results suggest that three MSHs (alpha-, beta-, and gamma-MSH) and a single END were established in ancestral invertebrates. Thereafter, unequal crossing over may have resulted in class-specific numbers of MSH segments during the radiation of fish. Moreover, duplication of the entire POMC gene may have led to the differentiation of POMC as shown in lampreys; one of the two subtypes is a precursor for ACTH and beta-END, the other is a precursor for two forms of MSH and the other form of beta-END. On the other hand, at least five subtypes of MC receptor (MCR) have been observed in fish. These are G-protein-coupled receptors with seven transmembrane domains. The ancestral MCR is suggested to have appeared before vertebrates, and then MCRs may have diverged by genome duplication and local duplication of each receptor gene during the evolution of vertebrates. They are distributed in many tissues in rather a subtype-specific manner and are responsible for a variety of biological functions. Thus, MC systems may have diverged by producing structurally different MC peptides from POMC and expressing MCR subtypes differing in ligand selectivity in a variety of tissues. (c) 2005 Elsevier Inc. All rights reserved.