Breast cancer cells express the chemokine receptor CXCR4 and frequently metastasize to organs with an abundant source of the CXCR4 ligand, stromal cell-derived factor 1 (SDF-1). The chemokine receptor CXCR4 plays an active role in the metastasis of breast cancer. Here, we show that a small interfering RNA (siRNA) against CXCR4 effectively downregulates CXCR4 expression in human MDA-MB-231 breast cancer cells, leading to significant decrease in breast cancer cell invasion and adhesion. It was further found that tumor cells lacking CXCR4 expression proliferated at a much slower rate than control cells in vitro. Surprisingly, tumor cells lacking CXCR4 expression failed to grow in SCID mice in repeated experiments, providing the first direct evidence for an essential role of CXCR4 in breast cancer growth in vivo. This finding suggests an expanded role for the CXCR4 molecule in tumor cell growth in vivo, in addition to its role in breast cancer metastasis. This study implies the CXCR4 molecule as a potential target to control breast tumor growth as well as metastasis.