The role of nitric oxide (NO) as a highly diffusible free radical gaseous vasodilator is intrinsically linked to the control of blood flow and oxygen (O(2)) delivery to tissue. NO also is involved in regulating mitochondrial O(2) metabolism, growth of new blood vessels, and blood oxygenation through control of respiratory ventilation. Hemoglobin and myoglobin may help to conserve NO for subsequent release of a NO-related vasoactive species under hypoxic conditions. NO has a major role in regulating microvascular O(2), and dysfunctional NO signaling is associated with the pathogenesis of metabolic and cardiovascular diseases.