Abstract Cancer progression is a complex process that involves tumor growth at the primary site coupled with metastatic colonization and outgrowth at a distant organ site. In the case of solid tumors, 90% of deaths are known to occur from metastasis. Searching for mediators of breast cancer progression and metastasis, we identified a signature of 18 genes, the expression of which in primary tumors could predict the risk of lung metastasis recurrence in over 700 breast cancer patients. The sole chemokine in the lung metastasis signature is CXCL1, a member of the C-X-C family of chemokines. We find that increased expression of CXC family members could be explained in part by amplification of 4q21, a locus that harbors CXCL1-8 in breast tumors and metastases that we examined. Investigating the functional role of the C-X-C family in breast cancer metastasis led us to uncover a series of paracrine interactions mediated by CXCL1 and CXCL2 with components of the tumor microenvironment. Using breast cancer cell lines, primary patient derived cells and transgenic mouse models of mammary cancer and lung metastasis, we show that CXCL1/2 serve dual functions promoting both primary tumor growth and lung metastasis. We also demonstrate that CXCL1/2 recruits myeloid subpopulations that are essential in mediating cancer cell survival. Using small molecule inhibitors targeting CXCL1/2 signaling, we elucidate that this chemokine axis is critical in mediating breast cancer metastasis to lung and can be pharmacologically targeted. The standard treatment for metastatic breast cancer is a combination of chemotherapeutic drugs. Disappointingly, these therapies only provide limited benefit and almost always result in relapse with acquired resistance and deadly consequences. We found that CXCL1, CXCL2 and other related family members were frequently upregulated in breast cancer models exposed to a variety of cytotoxic agents such as doxorubicin and taxanes. Moreover, our study revealed previously unknown tumor-stroma interactions that are initiated by CXCL1/2 in response to chemotherapy. Additionally, our functional studies in animal models and clinical evidence from patient samples demonstrated a function of CXCL1/2 in mediating chemoresistance. Interestingly, pharmacological inhibition of the CXCL1/2 paracrine axis in combination of chemotherapy significantly sensitized breast tumors to the therapy. In particular, combined treatment dramatically reduced the outgrowth of cancer cells at the lung metastatic site. Together, our findings reveal a network of tumor-microenvironment interactions mediated by the CXC chemokine axis that promotes tumor growth and metastasis on one hand and chemoresistance on the other.