There is increasing evidence that cancers develop as aberrant tissues with co-evolving tumor and surrounding non-malignant cells rather than from a single aberrant cell that has undergone multiple genetic alterations. As a result, different cellular components of the tumor mass are involved in a highly complex molecular crosstalk. However, all of the underlying molecular mechanisms of these interactions are not fully identified. Here, I have used genome-wide analysis to identify genes that mediate functional interactions between breast cancer cells and fibroblasts using a model system that allows for both genomic analysis and genetic manipulation of epithelial and stromal compartments. I've established through extensive bioinformatics analysis that this system reflects stromal alterations that occur in human primary breast cancers. RNAi analyses and a co-injection tumorigenicity assay were used to functionally validate genes involved in breast epithelial-stromal fibroblast interactions. I found that the majority of the genes surveyed mediated significant yet diverse roles in promoting cancer in vivo. Previous functional analyses have emphasized single genes or single processes as being the key players in tumor-promoting properties of fibroblasts but did not take a systematic genome-wide approach. Our results indicate there are instead multiple genes and processes involved in fibroblast promotion of breast cancer, providing multiple targets for therapeutic inhibition.