Vascular tone represents the balance between local vasodilator mechanisms which attempt to secure adequate blood flow for metabolic demand and neural vasoconstrictor reflexes attempting to maintain arterial pressure. Hypoxia alters vascular tone, shifting this balance in complex ways. Hypoxic vascular responses are not uniform across vascular beds and the mechanisms of hypoxic vasodilation appear to be tissue specific. In healthy humans, skeletal muscle vascular beds exhibit a graded vasodilation in response to hypoxia despite increases in sympathetic vasoconstrictor nerve activity. Previous studies have documented a number of vasodilator substances or systems that appear to be involved in this hypoxic vasodilation. My colleagues and I have conducted studies on the extent to which sympathetic vaso- constriction can mask hypoxic vasodilation, and how sympathetic vasoconstrictor activity interacts with local factors that mediate hypoxic vasodilation in humans. We have focused largely on β-adrenergic mediated vasodilation, noting that it produces some of its effects via a nitric oxide (NO) pathway. This review will explore the role of epinephrine in generating skeletal muscle vasodilation. How the many factors that determine vascular tone during hypoxic stress impact on the regulation of arterial pressure and how hypoxic vasodilation is altered in several pathophysiological conditions will be discussed.