Most of the syndromes that were initially linked to cancer were due to tumor suppressor genes and they often involved the intramural program at NCI. After the germline mutations were identified for retinoblastoma, Wilms tumor, and Li-Fraumeni syndrome, the NCI and NINDS contributed families with neurofibromatosis 1 and 2 to groups that eventually cloned the genes. The clinical and laboratory studies of Marston Linehan and Burt Zbar culminated in their discovery of several genes responsible for hereditary forms of renal cancer, starting with von Hippel-Lindau syndrome. The work of Peggy Tucker and Alisa Goldstein in hereditary melanoma led to their discovery of germline mutations of the tumor suppressor gene CDKN2A, and later the proto-oncogene CDK4. Our studies of familial breast cancer focused in the Ashkenazi Jewish population shed light on the role of founder mutations of BRCA 1 and BRCA 2. In addition, our families with the multiple basal cell carcinoma syndrome were studied by Mike Dean, who uncovered germline mutations of the patch gene. Since 1996 when I stopped making this slide, more than 50 inherited gene mutations involving tumor suppressors, proto-oncogenes, and mismatched repair genes have been identified through studies of these hereditary syndromes. And this information has greatly enhanced our understanding of the genetic and molecular mechanisms that are involved both in cancer etiology and progression.