ABSTRACT Cancers are extremely complex and variable, however a common feature appears to be the presence of critical driver events (e.g. genetic mutations in tumor suppressors) that drive tumor formation and progression. Key driver events, such as mutations in TP53, have been identified in many well-studied tumors. However, many human solid tumors do not have clearly identified driver events, even after common oncogenes and tumor suppressors have been systematically examined. We have termed this the “missing driver” problem. Our bioinformatics based approach to identify cancer driver events is to use innovative analyses of forward genetic screens for tumor formation in mice to identify genomic locations to systematically and exhaustively investigate within the increasing amounts of human cancer tumor genome-wide data in both publicly available as well as data generated within our lab. We expect to identify novel driver events and that the elucidation of the complete spectrum of tumor driver events will be extremely important to personalized approaches to cancer.