Abstract In the past five years, it has become possible to identify all of the mutations contributing to neoplasia in an individual cancer, leading to a deeper understanding of the pathogensis of neoplasia. The challenge now is to exploit this wealth information to reduce cancer deaths. Most current efforts towards this goal are focused on curing patients with advanced disease through “personalized” medicine approaches. However, the barriers to curing such patients are now being recognized, in part through the insights gained from cancer genome sequencing. Alternative strategies to reduce cancer deaths are therefore essential to achieving this goal. Fortunately, it is now clear that there are only ~150 genes, operating through ~12 well-recognized pathways, that drive the initiation and progress of the most common types of human cancers. These genes and pathways provide enormous opportunities for the early detection of neoplasia through sophisticated genomic, proteomic, and imaging-based technologies. Widespread implementation of early detection and prevention methods has the capacity to reduce cancer deaths by more than 75% in the foreseeable future. Citation Format: Bert Vogelstein, Kenneth W. Kinzler. Cancer Genomes and their Implications for Early Detection. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr DL01-01.