Notch signaling is used to choose cell fates in many developmental contexts. New evidence shows that circulating blood cells in Drosophila, in the absence of Notch ligand provided by neighboring cells, activate Notch signaling through stabilization with the hypoxia-inducible factor-α (HIF-α) transcription factor. Although HIF-α is a key regulator of the low-oxygen stress response, here it acts without its HIF-β partner by interacting with and stabilizing the Notch receptor. These roles for HIF-α and Notch are atypical in multiple ways, from the activity of HIF-α under normal oxygen tensions and without its partner HIF-β to the ligand-independent activity of Notch, and serve as a challenge to identify other noncanonical uses of well-studied signaling pathways.