The CXCL12-CXCR4 axis is postulated to be a key pathway in the interaction between (cancer) stem cells and their surrounding supportive cells in the (cancer) stem cell niche. As the bone marrow constitutes a unique microenvironment for cancer cells, the CXCL12-CXCR4 axis assists the bone marrow in regulating cancer progression. This interaction can be disrupted by CXCR4 antagonists, and this concept is being used clinically to harvest hematopoietic stem/progenitor cells from the bone marrow. The functions of CXCL12-CXCR4 axis in cancer cell-tumor microenvironment interaction and angiogenesis have been recently studied. This review focuses on how CXCL12-CXCR4 helps the bone marrow in creating a tumor mircoenvironment that results in the cancer metastasis. It also discusses ongoing research regarding the clinical feasibility of CXCR4 inhibitors.