Abstract Learning Objectives After completing this course, the reader will be able to: Assess CXCR4 expression in the primary tumor for use as an indicator of a higher risk for bone metastasis in early breast cancer.Evaluate the relationship between CXCR4 expression and the occurrence of metastases in other SDF-1–producing organs, including the liver and lung.Use CXCR4 in different ways in combination with other markers to identify patients to be screened for bony metastases and/or treated preventatively for bone metastasis. This article is available for continuing medical education credit at CME.TheOncologist.com. Background. Chemokine receptor 4 (CXCR4) has been demonstrated to have a critical role in the early metastatic process. The aim of this study was to evaluate the prognostic value of CXCR4 expression in primary breast tumors and describe correlations with the occurrence of metastasis in organs expressing the CXCR4 ligand stromal cell–derived factor 1 (i.e., liver, lung, brain, and bone). Patients and Methods. CXCR4 expression in primary breast tumors was evaluated by immunohistochemistry in 823 patients included in two prospective clinical trials. CXCR4 expression was considered positive when >1% of tumor cells were stained. The prognostic value of CXCR4 expression was assessed by a Cox regression model adjusted for clinical characteristics. We assessed the association of CXCR4 expression with the rate of distant metastasis to specific organ sites. Results. CXCR4 was expressed in 92 of 794 primary tumors (12%). CXCR4 expression was not associated with clinical characteristics. CXCR4 was not prognostic for overall survival and showed a nonsignificant trend toward a higher risk for distant metastasis. CXCR4+ tumors showed a significantly higher risk for bone metastasis. The 10-year incidences of bone metastases were 23% (13.6%–32.6%) and 12% (9.7%–15%) in CXCR4+ and CXCR4− tumors, respectively. Conclusion. This study suggests that expression of CXCR4 in primary breast tumors is associated with a higher likelihood of developing bone metastases. This finding could open new avenues for the development of novel adjuvant strategies, including bone-targeting agents.