ID2 and hypoxia-inducible factor 2α (HIF2α) promote several characteristics of cancer stem cells, but the molecular pathways that connect the two are unclear. Lee et al. show that dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) and DYRK1B phosphorylate ID2 in normoxia (but not in hypoxia). Phosphorylated ID2 is unable to bind to von Hippel–Lindau tumour suppressor (VHL), which consequently promotes HIF2α degradation. Thus, unphosphorylated ID2 promotes HIF2α activity, which can be reversed (and tumour growth inhibited) when DYRK1 kinases are overexpressed; DYRK1 expression in glioblastoma correlated with good prognosis.