Melanoma is derived from genetic changes affecting melanocytes which arise from neural crest-derived progenitor cells that migrate from the developing central nervous system into the skin. This chapter highlights both genetic changes associated with hereditary cutaneous melanoma, as well as highlight some aspects of the genetic role of disease progression. Melanoma can be classified into four distinct subtypes based upon clinical and histological features: superficial spreading melanoma, lentigo maligna melanoma, acral lentigious melanoma and nodular melanoma. Since the 1930s, the incidence of melanoma has increased nearly 20-fold. A number of precursor lesions may eventually turn into or increase the risk of malignant melanoma. The epidemiological evidence implicating sun exposure in the causation of melanoma is supported by biologic evidence, which suggests that damage caused by ultraviolet radiation, particularly damage to DNA, plays a central part in the pathogenesis of these tumors. The earliest report of melanoma and possible involvement of a hereditary component, may be that by W. Norris.