The activity of hypoxia-inducible factor 1 (HIF-1) is critical for many processes such as vascular growth control, metabolism, iron transport as well as haemoglobin synthesis. Beside the oxygen-dependent regulation of the regulative HIF-1alpha subunit, there is increasing evidence for non-oxygen dependent pathways causing HIF-1 activation. In this study we addressed the question as to whether or not the stability of the HIF-1alpha mRNA is important for its regulation. Furthermore, we present a method to specifically identify RNA-binding proteins (RNA-BPs) that modulate mRNA stability of selected genes. Based on modelling and on the computational analysis of large-scale expression data of more that 1200 microarray experiments, we show that HIF-1alpha mRNA turnover is crucial for the activity of HIF-1 and expression of its downstream targets. We show that a number of RNA-binding proteins are correlated with HIF-1 target genes, and experimentally validated these data. Our data demonstrate that RNA-BPs modulate HIF-1a expression level and subsequently HIF-1 function under physiological and pathophysiological conditions.