The activity of the hypoxia-inducible factor 1 (HIF-1) is mainly controlled by expression levels of the regulatory alpha subunit. HIF-1 target genes are involved in a broad range of cellular processes such as angiogenesis, extra cellular matrix remodeling, glycolysis, and inflammation. It has been demonstrated that activation of HIF-1 is crucial for survival and function of immune cells. The aim of this study was to elucidate regulative mechanisms involved in HIF-1 activation during macrophagocytic differentiation. We used a model of human monocytic THP-1 cells, which were treated with phorbol ester to induce cellular differentiation. It turned out that elevated HIF-1a levels are mainly attributable to enhanced HIF-1a mRNA stability under these circumstances. We therefore systematically analyzed the HIF-1a mRNA 3'untranslated region (3'UTR) and show that the 3'UTR of HIF-1a mRNA belongs to the top <0.001% of all mRNA 3'UTRs with highly conserved information content. Furthermore, the HIF-1a mRNA 3'UTR contains numbers of AU-rich elements, indicating a pivotal role of mRNA stability in the control of HIF-1 functions. By UV-cross-linking, mRNA-stability assays, RNAi knock-down and pharmacological intervention, we demonstrate that RNA-binding proteins modulate HIF-1a mRNA turnover during monocyte to macrophage differentiation. We conclude that posttranscriptional control of HIF-1a synthesis is crucial for HIF-1 activation, which in turn is critical for macrophage function. Our findings provide new insights into the molecular mechanisms involved in macrophage mediated inflammatory angiogenesis, arteriogenesis and tumor growth.