Hypoxia-inducible factors (HIF)-1 and HIF-2 are master regulators of oxygen homeostasis that regulate the expression of thousands of genes in order to match O₂ supply and demand. A large body of experimental data links HIF activity to protection against multiple disorders affecting the cardiovascular system: ischemic cardiovascular disease (including coronary artery disease and peripheral artery disease), through collateral blood vessel formation and preconditioning phenomena; emphysema; lymphedema; and lung transplant rejection. In these disorders, strategies to increase the expression of one or both HIFs may be of therapeutic utility. Conversely, extensive data link HIFs to the pathogenesis of pulmonary arterial hypertension and drugs that inhibit one or both HIFs may be useful in treating this disease.