The most well-known receptor on melanocytes that modulates their function is the melanocortin-1 receptor (MC1R), activation of which increases cAMP production that leads to the phosphorylation of cAMP responsive-element-binding protein (CREB) transcription factor family members.

The downstream target of MC1R, e.g. cAMP levels, can be decreased by androgens in combination with sex-hormone binding globulin, although drawbacks to this approach include a weak hypopigmenting effect and side effects of the agents.

Agonists of the MC1R include α-melanocyte-stimulating hormone (α-MSH) and adrenocorticotropic hormone (ACTH), while the only known antagonist of the MC1R is agouti signal protein (ASP), which modulates switch from eu- to pheo-melanogenesis.  However, the specific mechanism regulating this switch has yet to be elucidated.

Polymorphisms of MC1R have been extensively investigated with respect to their roles in responses to UV radiation and/or in controlling constitutive skin pigmentation among racial/ethnic groups.