The laboratory mouse is one of the most powerful tools for both gene discovery and validation in cancer genetics. Recent technological advances in engineering the mouse genome with chromosome translocations, latent alleles, and tissue-specific and temporally regulated mutations have provided more exacting models of human disease. The marriage of mouse tumor models with rapidly evolving methods to profile genetic and epigenetic alterations in tumors, and to finely map genetic modifier loci, will continue to provide insight into the key pathways leading to tumorigenesis. These discoveries hold great promise for identifying relevant drug targets for treating human cancer.