New research offers mechanistic and clinical insights into CXC chemokine receptor 4 (CXCR4) nuclear localization in renal cell carcinoma (RCC). CXCR4 nuclear localization — which frequently occurred in RCCs, particularly metastases — was associated with poor prognosis and induced metastasis in vitro and in vivo. A mechanistic feedforward loop was identified whereby nuclear CXCR4 promoted hypoxia-inducible factor 1α (HIF-1α) accumulation, which, in turn, induced CXCR4 transcription. Clinically, CXCR4 and HIF-1α subcellular expression levels were associated with poor prognosis independently and when combined with TNM stage.