Although a highly structural homology exists between HIF-1α and HIF-2α, these transcription factors may also be differently regulated and transactivate common and unique targeted gene products in a cancer cell-dependent manner under normoxic and hypoxic conditions (Fig. 3) [16, 20, 24, 89, 106, 107, 117, 120, 121–125]. The gene discussed is EPAS1; the disease is cancer.