Tumorigenesis and metastasis are complex multistep processes. In addition to the numerous somatic mutations that facilitate cancer progression, there is abundant evidence that an individual's genetic background not only contributes to overall cancer risk, but also specifically influences metastatic potential. The handful of human susceptibility genes that have been identified thus far do not fully account for hereditary cancer risk, and the discovery of additional susceptibility loci using population based studies is complex, time-consuming and expensive. Therefore, we and others have used a variety of mouse models to identify novel candidate susceptibility genes. Here we review how these mouse models have contributed to our understanding of the role of genetic background in modifying tumorigenesis and metastasis susceptibility.