Metastasis and resistance to chemotherapy co-occur in cancer, although the molecular links between them are not understood. Previous data suggested that increased expression of CXCL1 and CXCL2 has an important role in breast cancer metastasis, and Joan Massagué and colleagues now report that these chemokines mediate a signaling network that links lung metastasis and chemotherapy resistance in breast cancer (Cell 150, 165–178, 2012). The authors knocked down CXCL1 and CXCL2 in a metastatic lung cancer xenograft model and analyzed the tumor microenvironment, finding that there were fewer CD11b+Gr1+ myeloid cells than in controls. Hypothesizing that these cells might secrete paracrine factors that augment cancer cell survival, the authors found that expression of the paracrine factors S100A8 and S100A9 correlates with that of CXCL1 in breast cancer. Mammary tumor growth and lung metastasis were decreased in S100a9−/− mice, suggesting that S100A8 and S100A9 are required for tumor cell survival and metastasis. The authors analyzed breast tumors before and after chemotherapy and observed an increase in S100A9 after treatment. Chemotherapy also induces tumor necrosis factor (TNF)-α in stromal cells, which further amplifies the CXCL1/CXCL2-S100A8/S100A9 pathway in tumor cells. Preclinical work in mouse models showed that chemotherapy combined with treatment with a CXCR2 antagonist might be an effective way to reduce tumor growth.