Coronary vascular resistance is regulated by a variety of factors including arterial pressure, myocardial metabolism, autonomic nervous system as well as arterial O2 tension (hypoxia). Progressive hypoxemia results in graded coronary vasodilation that is significantly more pronounced when arterial O2 tension falls below 40 mmHg. Microvascular studies have demonstrated that O2 has direct effects on vascular smooth muscle likely mediated by O2 sensors located in vessels < 15 μm diameter. Recent data indicates that hypoxia-induced inhibition of the pentose phosphate pathway and the subsequent decreases in NADPH and intracellular Ca2+ represent an important O2 sensing mechanism in vascular smooth muscle. However, in vivo experiments suggest direct microvascular effects of O2 contribute little to hypoxic coronary vasodilation. The vasodilation is mediated, in part, by local vasoactive metabolites produced in proportion to the degree of hypoxemia, reflex-mediated increases in myocardial metabolism and diminished myocardial tissue oxygenation. In particular, production of adenosine has been shown to increase exponentially with the degree of hypoxia and blockade or degradation of adenosine markedly impairs hypoxia-induced coronary vasodilation. Other investigations support the role of endothelial derived relaxing factors (nitric oxide, prostacyclin) in control of coronary blood flow during hypoxia. Additionally, reductions in PO2 hyperpolarize coronary vascular smooth muscle via K+ ATP channels which represent important "end effectors" that significantly contribute to hypoxic coronary vasodilation. Taken together, these data indicate that the coronary vascular response to hypoxia depends on metabolic and endothelial vasodilatory factors that are produced in proportion to the degree of hypoxemia and that function through mechanisms depending on KATP+ channels.