The precursor protein proopiomelanocortin (POMC) produces many biologically active peptides via a series of enzymatic steps in a tissue-specific manner, yielding the melanocyte-stimulating hormones (MSHs), corticotrophin (ACTH) and beta-endorphin. The gene for alpha-MSH is encoded for by the POMC gene, but alpha-MSH cannot be produced from POMC gene transcription and translation without these specific post-translational proteolytic steps taking place. The MSHs and ACTH bind to the extracellular G-protein-coupled melanocortin receptors (MCR), of which there are five subtypes. Two (MC1R and MC5R) show widespread cutaneous expression. ACTH and alpha-MSH bind to MC1R to influence both pigmentation and the immune system. MC5R regulates the sebaceous glands. Mutations in the MC1R gene lead to fair skin and red hair in humans, which is also seen with inactivating human POMC gene mutations. MC1R mutant receptor expression can also correlate with an increased incidence of the three commonest forms of skin cancer. Other mutations can occur in the POMC system or parallel interacting pathways, such as in prohormone convertase 1 and agouti signalling protein, a human homologue of murine agouti protein. However, they do not necessarily affect skin colour or function in humans, and further studies are needed to clarify these observations.