Cutaneous basal and squamous cell carcinomas are among the most frequent malignancies in the white population, with the annual incidence estimates ranging from 1 million to 3.5 million cases in the United States. These tumors can occur either sporadically or in the context of hereditary genodermatoses with cancer predisposition, such as basal cell nevus syndrome, xeroderma pigmentosum, epidermolysis bullosa, or oculocutaneous albinism. Different genes and signaling pathways have been shown to play a central role in the development and growth of these tumors. This article overviews the clinical features, diagnostic criteria, and the most recent data on genetic routes of the major hereditary syndromes predisposed to the development of nonmelanoma skin cancer.