The study investigates the regulation of the chemokine receptor CXCR4 by hypoxia (Hyp). It is found that low oxygen concentrations induce high expression of CXCR4 in various cell types, including monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells. This induction is dependent on the activation of hypoxia-inducible factor 1α (HIF-1α) and transcript stabilization. The Hyp–HIF-1α–CXCR4 pathway may regulate the trafficking and localization of cells in hypoxic tissues, potentially playing a role in inflammatory and neoplastic diseases. The study also demonstrates that HIF-1α is involved in the hypoxic induction of CXCR4 expression, as shown by the impaired induction in HIF-1α knockout cells and the increased CXCR4 expression in cells treated with the HIF-1α inhibitor Topotecan. Additionally, the Hyp-induced stabilization of CXCR4 mRNA contributes to its increased expression. These findings highlight the Hyp–HIF-1α–CXCR4 pathway as a critical molecular circuit in the functional tuning of the chemokine system, with potential implications for therapeutic strategies.The study investigates the regulation of the chemokine receptor CXCR4 by hypoxia (Hyp). It is found that low oxygen concentrations induce high expression of CXCR4 in various cell types, including monocytes, monocyte-derived macrophages, tumor-associated macrophages, endothelial cells, and cancer cells. This induction is dependent on the activation of hypoxia-inducible factor 1α (HIF-1α) and transcript stabilization. The Hyp–HIF-1α–CXCR4 pathway may regulate the trafficking and localization of cells in hypoxic tissues, potentially playing a role in inflammatory and neoplastic diseases. The study also demonstrates that HIF-1α is involved in the hypoxic induction of CXCR4 expression, as shown by the impaired induction in HIF-1α knockout cells and the increased CXCR4 expression in cells treated with the HIF-1α inhibitor Topotecan. Additionally, the Hyp-induced stabilization of CXCR4 mRNA contributes to its increased expression. These findings highlight the Hyp–HIF-1α–CXCR4 pathway as a critical molecular circuit in the functional tuning of the chemokine system, with potential implications for therapeutic strategies.