The melanocortin 1 receptor (MC1R) gene encodes for a seven-pass transmembrane 
receptor primarily expressed on melanocytes and melanoma cells. Single 
nucleotide polymorphisms (SNPs, also termed variants) in MC1R frequently cause 
red hair, fair skin and are associated with melanoma and keratinocyte-derived 
skin cancer development. Activation of wild-type (WT) MC1R in skin assists 
cutaneous photoprotection whereas reduced MC1R signalling, seen with MC1R 
variants, impairs ultraviolet radiation (UVR)-protective responses. As ancestral 
humans migrated out of Africa, the evolutionary advantage of MC1R variants may 
have related to improved cutaneous vitamin D synthesis and higher birthweight 
reported with certain MC1R variants. Reduced photoprotection secondary to MC1R 
dysfunction involves pigmentary and non-pigmentary mechanisms (reduced DNA 
repair, effects on cell proliferation and possibly immunological parameters), 
leading to clonal expansion of mutated cells within skin and subsequent 
carcinogenesis. Recent investigations suggest an association between MC1R 
genotype and vitiligo, with preliminary evidence that a MC1R agonist, 
[Nle4-D-Phe7]-alpha-MSH, in combination with UVB, assists repigmentation. Future 
development of compounds to correct defective MC1R responses secondary to MC1R 
variants could result in photoprotective benefits for fair-skinned individuals 
and reduce their skin cancer risk.