Importance of the CXCR4 chemokine receptor and its ligand, CXCL12, in the tumor microenvironment and for targeted metastasis. Within hypoxic areas of tumors, both CXCL12 expression by fibroblasts and CXCR4 expression on tumor cells increases, which stimulates tumor cell motility and invasiveness. Carcinoma-associated fibroblasts (CAFs), but not normal fibroblasts, stimulate tumor progression by CXCL12 secretion. Two major mechanisms by which fibroblast-derived CXCL12 promotes tumor genesis have been identified. First, CXCL12 promotes tumor cell growth in a paracrine fashion by directly stimulating tumor cell growth via CXCR4. Second, CXCL12 from CAFs induces recruitment of endothelial progenitors, which allow for tumor angiogenesis (endocrine effect of CXCL12). Targeted metastasis to the marrow or other sites of high CXCL12 expression involves CXCR4 activation on circulating tumor cells that “hijack” the CXCR4-CXCL12 axis for homing to microenvironments that normally are restricted to hematopoietic progenitor cells (HPCs). CXCL12 gradients attract CXCR4-positive tumor cells to marrow niches where marrow stromal cells secrete high levels of CXCL12. As a consequence, tumor cells can displace HPCs from their protective microenvironment, resulting in hematopoietic dysfunction. Moreover, tumor cells may invade adjacent tissues, resulting in bone destruction.