Breast tumors are characterized by an extensive desmoplastic stroma, abundantly populated by fibroblasts. Cancer-associated fibroblasts (CAF) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. CAF also orchestrate tumor-promoting inflammation in multiple tumor types including breast cancer. However, the mechanisms through which normal tissue fibroblasts are reprogrammed to tumor-promoting CAFs are mainly obscure. Here we show that mammary fibroblasts can be educated by breast cancer cells to become activated to a pro-inflammatory state that supports malignant progression. Proteomic analysis of breast cancer cell-secreted factors identified the secreted pro-inflammatory mediator Osteopontin (OPN), which has been implicated in inflammation, tumor progression and metastasis. OPN was highly secreted by mouse and human breast cancer cells, and tumor cell secreted OPN activated a CAF phenotypes in normal mammary fibroblasts in vitro and in vivo. OPN was sufficient to induce fibroblast reprogramming and neutralizing antibodies against OPN blocked fibroblast activation induced by tumor cells. The ability of secreted OPN to activate mammary fibroblasts relied upon its known receptors CD44 and αVβ3 integrin. Strikingly, OPN silencing in tumor cells in vivo attenuated stromal activation and inhibited tumor growth. Our findings establish a critical functional role for paracrine signaling by tumor-derived OPN in reprograming normal fibroblasts into tumor-promoting CAFs.