Through scientific and technological advancements, our ability to manipulate the mouse genome has allowed us to evaluate the effect of specific genetic alterations on in vivo tumorigenesis. This has allowed and will allow us to define molecular pathways describing the processes of tumor initiation, invasion, and progression to metastatic disease. Additionally, these models may serve as an excellent platform for the identification of novel molecular targets for therapy as well as to evaluate the efficacy of targeted therapies. Ultimately this will translate from preclinical mouse model trials to the development of clinical trials and protocols for cancer patients. Here we review the usefulness of mouse modeling in oncologic translational research.