Hyperactivation of Notch signaling and the cellular hypoxic response are frequently observed in cancers, with increasing reports of connections to tumor initiation and progression. The two signaling mechanisms are known to intersect, but while it is well established that hypoxia regulates Notch signaling, less is known about whether Notch can regulate the cellular hypoxic response. We now report that Notch signaling specifically controls expression of HIF2 alpha, a key mediator of the cellular hypoxic response. Transcriptional upregulation of HIF2 alpha by Notch under normoxic conditions leads to elevated HIF2 alpha protein levels in primary breast cancer cells as well as in human breast cancer, medulloblastoma, and renal cell carcinoma cell lines. The elevated level of HIF2 alpha protein was in certain tumor cell types accompanied by downregulation of HIF1 alpha protein levels, indicating that high Notch signaling may drive a HIF1 alpha-to-HIF2 alpha switch. At the transcriptome level, the presence of HIF2 alpha was required for approximately 21% of all Notch-induced genes: among the 1062 genes that were upregulated by Notch in medulloblastoma cells during normoxia, upregulation was abrogated in 227 genes when HIF2 alpha expression was knocked down by HIF2 alpha siRNA. In conclusion, our data show that Notch signaling affects the hypoxic response via regulation of HIF2 alpha, which may be important for future cancer therapies.