The SUMO Signaling Group of IBCII find that SUMO signaling in hypoxia is altered by inactivation of SUMO-specific isopeptidases. Using proteomic analysis, we define a subset of hypoxia-induced SUMO1 targets and propose that hypoxia-induced SUMOylation of the transcriptional co- repressor BHLHE40 contributes to metabolic reprogramming under these conditions.