High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F(2) mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F(2) mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL x diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL x diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations.