The following sections will (i) summarize the clinical evidence for the involvement of HIFs in a variety of acute and chronic liver diseases, (ii) discuss the current understanding and knowledge gaps of the mechanistic involvement of HIF1α and HIF2α in the disease development and progression (Table 1), and (iii) highlight the potentials of activating or inhibiting HIFs as therapeutic interventions to treat various liver diseases (Table 2). The gene discussed is EPAS1; the disease is liver disorder.