Tumor hypoxia activates hypoxia-inducible factor-1 (HIF-1) and induces the accumulation of the tumor suppressor p53. HIF-1 signaling stimulates angiogenesis and mediates cellular adaptation to hypoxia, whereas p53 promotes hypoxia-induced apoptosis. A recent article provides in vitro biophysical evidence supporting a direct interaction between p53 and the oxygen-dependent degradation domain of the HIF-1alpha subunit. The article identifies potential structural parameters required for this interaction and suggests an alternative mechanism by which p53 might impact tumor response to therapy.