A melanoma predisposition gene has been identified. This gene, CDKN2, maps to chromosome 9p21-p22 and encodes p16, an inhibitor of cyclin-dependent kinases 4 and 6. CDKN2 has been found to be inactivated by homozygous deletion or intragenic mutation at high frequency in a diverse range of tumors and tumor cell lines, including those derived from melanomas. Now a number of CDKN2 mutations have been found in the germline of affected members of melanoma kindreds, and biochemical analysis of the mutant proteins has confirmed that they are functionally compromised. Unexpectedly, no germline CDKN2 mutations have been found in about half of the melanoma families that appear to be linked to 9p. Regulatory mutations outside of the coding region are being sought in these families. A number of other kindreds do not appear linked to 9p, hence the search continues for a second melanoma susceptibility gene.