Melanocytes are specialized cells responsible for producing and providing melanin pigment to mammalian skin and hair. The variation in human skin pigmentation has evolved through natural selection in response to ultraviolet radiation (UVR). For decades, the connection between UVR exposure and the incidence of melanoma has been appreciated. However, populations living in the same geographic region, and thereby exposed to similar amounts of UVR, exhibit large variations in the lifetime risk of cutaneous melanoma. By understanding the mechanisms by which melanoma differentially affects diverse populations, we may reveal new therapeutic approaches. In the United States, the risk of melanoma is 30 times higher in people with lightly pigmented skin versus darkly pigmented skin. Researchers have long suggested that this large fold difference cannot simply be explained by the UVR-protective effect of melanin pigment, but the specific mechanisms have remained unknown. During this thesis work, we show that lightly pigmented melanocytes (LMCs) have cell-intrinsic differences that cause them to be more susceptible to melanomagenesis than darkly pigmented melanocytes (DMCs). We go on to show that these differences result from dihydroxyphenylalanine (DOPA), a melanin synthesis intermediate, which is synthesized and secreted from DMCs at higher levels than LMCs. DOPA’s anti-proliferative effect is independent of melanin synthesis and exogenous DOPA can recapitulate DMC phenotypes in LMCs. Using complimentary pharmacologic and genetic in vivo screens, we found that DOPA limits melanocyte and melanoma cell proliferation through inhibition of muscarinic acetylcholine receptor M1 (CHRM1) signaling. We then determined that DOPA’s antagonism of CHRM1 converged on two transcription factors and major cell cycle regulators, FOXM1 and c-Myc. Systemic treatment of melanoma-bearing mice with specific novel FOXM1 inhibitors was tolerated and had dramatic anti-tumor effects, with some mice exhibiting complete and sustained tumor clearance. In conclusion, this work identified the first UV-independent cell-intrinsic mechanism by which highly pigmented melanocytes are protected against melanomagenesis, first to propose that DOPA regulates CHRM1 signaling, and discovered two novel therapeutic targets for melanoma, CHRM1 and FOXM1.