The chemokine receptor CXCR4 is involved in the metastasis of many cancers. Recent evidence suggests that CXCR4 may be also involved in the metastasis of renal cell carcinoma. We analyzed the expression of CXCR4 in primary carcinomas, metastatic tissues and normal tissues using immunohistochemistry. We further investigated the migration of renal carcinoma cells in response to stimulation by CXCL12 in vitro. We also studied the subcellular localization of CXCR4 in renal cell carcinoma cells in response to CXCL12 by confocal microscopy. We observed the highest percentage of CXCR4 expression in renal cell carcinoma metastases compared with that in renal cell carcinomas and normal renal tissues. We further found that CXCR4 was localized predominantly in the membrane in primary renal cell carcinomas and predominantly in the cytoplasm in renal cell carcinoma metastases. Moreover, we found that CXCR4 was translocated from the cytoplasmic membrane to the cytoplasm upon stimulation by its ligand CXCL12. Renal cell carcinoma metastasis was associated with higher expression of CXCR4 and interaction of CXCR4 and its ligand CXCL12 resulted in the internalization of CXCR4 from the cytoplasmic membrane. These findings implicate the CXCR4-CXCL12 axis in the metastasis of renal cell carcinoma.