The urgent need for better cancer treatments has stimulated interest in employing small-animal models to evaluate potential drug therapies. Robust mouse models of many human cancers have been generated using sophisticated technologies for engineering germ-line mutations. As we enter into an age of targeted therapeutics, these strains provide novel platforms for validating new anticancer drugs, assessing therapeutic index, identifying surrogate markers of tumor progression, and defining epigenetic and environmental influences on tumorigenesis.