Progression from normal to malignant phenotype involves aberrations in the reciprocal interactions of multiple cell types with each other and with other components of the microenvironment. In this issue of Cancer Cell, demonstrate that progression to breast cancer involves genotypic as well as gene expression changes that are cell type-specific, suggesting that targeted therapies delivered to the tumor may need to include drugs targeted not only to the tumor cells, but also to the other cell types in the tumor microenvironment.