Genetic susceptibility to nevi may affect the risk of developing melanoma, since common and atypical nevi are the main host risk factors implicated in the development of cutaneous melanoma. Recent genome-wide studies defined a melanoma polygenic risk score based on variants in genes involved in different pathways, including nevogenesis. Moreover, a predisposition to nevi is a hereditary trait that may account for melanoma clustering in some families characterized by cases with a high nevi density. On the other hand, familial melanoma aggregation may be due to a Mendelian inheritance of high/moderate-penetrance pathogenic variants affecting melanoma risk, regardless of the nevus count. Based on current knowledge, this review analyzes the complex interplay between nevi and melanoma predisposition in a familial context. We review familial melanoma, starting from Whiteman’s divergent pathway model to overall melanoma development, distinguishing between nevi-related (cases with a high nevus count and a high polygenic risk score) and nevi-resistant (high/moderate-penetrance variant-carrier cases) familial melanoma. This distinction could better direct future research on genetic factors useful to identify high-risk subjects.