Hypoxic conditions in all human cells are counteracted by hypoxia inducible factor-1 alpha (HIF-1α) stabilization and subsequent transcription of genes that upregulate cell growth, migration/invasion, and survival.97–101 Through HIF activity, cancer cells acquire many malignant properties, including metabolic adaptation and runaway proliferation.101 Because Ref-1/APE1 redox signaling promotes HIF-1 transactivation,14, 18 the interplay between HIF-1 and Ref-1/APE1 presents vast opportunity for therapeutic manipulation. The gene discussed is SETD2; the disease is cancer.