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While exposure to ultraviolet radiation is a key environmental risk factor for melanoma, up to ~10% of patients report a family history of melanoma, and ~1% have a strong family history. The understanding of causal mutations in melanoma has been critical to the development of novel targeted therapies that have contributed to improved outcomes for late\u2010stage patients. Here, we review current knowledge of the genes affected by familial melanoma mutations and their partial overlap with driver genes commonly mutated in sporadic melanoma development. One theme linking a set of susceptibility loci\/genes is the regulation of skin pigmentation and suntanning. The largest functional set of susceptibility variants, typically with high penetrance, includes <jats:italic>CDKN2A<\/jats:italic>, <jats:italic>RB1<\/jats:italic>, and telomerase reverse transcriptase (<jats:italic>TERT<\/jats:italic>) mutations, associated with attenuation of cell senescence. 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