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Activation of the hypoxia‐inducible factor α‐subunits, HIF‐1α and HIF‐2α, seems to be subject to similar regulatory mechanisms, and transgene approaches suggested partial functional redundancy. Here, we used RNA interference to determine the contribution of HIF‐1α vs. HIF‐2α to the hypoxic gene induction. Surprisingly, most genes tested were responsive only to the HIF‐1α siRNA, showing no effect by HIF‐2α knock‐down. The same was found for the activation of reporter genes driven by hypoxia‐responsive elements (HREs) from the erythropoietin (EPO), vascular endothelial growth factor, or phosphoglycerate kinase gene. Interestingly, EPO was the only gene investigated that showed responsiveness only to HIF‐2α knock‐down, as observed in Hep3B and Kelly cells. In contrast to the EPO‐HRE reporter, the complete EPO enhancer displayed dependency on HIF‐2α regulation, indicating that additional cis …