Renal cell carcinoma (RCC) shows organ-specific metastasis. This may be attributed to the fact that the CXCR4 G protein coupled receptor on RCC cells mediates chemo-attraction toward stromal-derived factor (SDF)-1 secreted by target organs. SDF-1 binding to CXCR4 initiates many internal signaling cascades as well as internalization of the receptor complex. Here we show that SDF-1 binding localized CXCR4 to the nucleus in A-498 renal carcinoma cells over a 24 h period. CXCR4 nuclear localization in A-498 cells associated with increased Matrigel matrix invasion, a metastatic trait. Comparing histological sections of primary and metastatic human RCC, we found that CXCR4 localized to the nucleus only in metastatic RCC lesions. In conclusion, SDF-1 binding of CXCR4 not only induces immediate signaling via signaling cascades, but also a slower response via nuclear localization of the receptor complex. CXCR4 nuclear localization may be responsible for certain metastatic changes in cancer cells and can be used to distinguish metastatic RCC cells. These findings may be applied to the search for ways to inhibit RCC, as well as to many other questions that involve CXCR4 such as normal hematopoiesis, tissue regeneration, stem cell research and HIV infection.