The first description of familial melanoma in the English literature appeared in 1820, when Norris (1) reported: It is remarkable that this gentleman's father, about thirty years ago, died of a similar disease.... This tumour, I have remarked, originated in a mole, and it is worth mentioning, that not only my patient and his children had many moles on various parts of their bodies, but also his own father and brothers had many of them.... These facts, together with a case that has come under my notice, rather similar, would incline me to believe that this disease is hereditary. Since then, many families with a predisposition to melanoma have been described worldwide (2-5). For purposes of case definition, our laboratory curently defines familial melanoma (FMM) as a family containing >2 affected first-degree relatives with melanoma and/or pancreatic carcinoma. According to this definition, about 8-12% of melanoma is inherited as an autosomal dominant trait with variable penetrance. Affected members (AFM) of these FMM kindreds may develop multiple primary melanoma (6) and/or pancreatic cancer (7) and typically present at an earlier age than do patients with sporadic disease. In a subset of such individuals and kindreds, germline mutations of the CDKN2A gene (also known as p16INK4A and MTS1) cosegregate with cases of melanoma (2-5).We have hypothesized that the identification of mutation carriers may in the future allow us to direct resources to the prevention and surveillance of mela noma in high-risk individuals and families. This chapter provides an overview of melanoma genetics, as well as the indications, drawbacks, and methods of germline CDKN2A mutation screening by polymerase chain reaction (PCR) amplification and automated sequencing of genomic DNA.