Hypoxia can have profound influences on the circulation. In humans, acute exposure to moderate hypoxia has been demonstrated to result in vasodilation in the coronary, cerebral, splanchnic and skeletal muscle vascular beds. The combination of submaximal exercise and hypoxia produces a “compensatory” vasodilation and augmented blood flow in contracting muscles relative to the same level of exercise under normoxic conditions. This augmented vasodilation exceeds that predicted by a simple sum of the individual dilator responses to hypoxia alone and normoxic exercise. Additionally, this enhanced hypoxic exercise hyperemia is proportional to the hypoxia-induced fall in arterial oxygen (O2) content, thus preserving muscle O2 delivery and ensuring it is matched to demand. Several vasodilator pathways have been proposed and examined as likely regulators of skeletal muscle blood flow in response to changes in arterial oxygen content. The purpose of this talk is to put into context the present evidence regarding mechanisms responsible for the local control of blood flow during acute systemic hypoxia in contracting muscle. Specifically this talk will highlight the roles of nitric oxide (NO) and adenosine as potential vasodilator signals in hypoxia dependent skeletal muscle vasodilation. In general NO has been implicated as a key vasodilator signal in resting skeletal muscle in response to acute hypoxia in humans and animals. Studies have demonstrated that NO synthase (NOS) inhibition attenuates the hypoxic vasodilator response in the human forearm and arterioles of rat skeletal muscle. Evidence in animals suggests that a portion of the NO-mediated hypoxic vasodilation is due to adenosine receptor activation. However, available data related to the contribution of adenosine in the hypoxic vasodilator response in human studies are conflicting. In this context, interstitial levels of adenosine are elevated in response to acute hypoxia, whereas adenosine receptor antagonism does not appear to attenuate hypoxia mediated vasodilation. Similar roles for NO and adenosine have been reported during hypoxic exercise in humans. Along these lines, there is a significant blunting of the compensatory vasodilation in the forearm during mild to moderate hypoxic exercise after NOS inhibition. Conversely, adenosine receptor antagonism does not alter skeletal muscle blood flow and vasodilation in the contracting human forearm or leg during hypoxic exercise. Taken together, the data to be discussed during this talk suggests that NO contributes to hypoxia mediated vasodilation in resting and contracting skeletal muscle. By contrast, the role of adenosine in hypoxic dependent vasodilation is not completely clear. Adenosine appears to contribute to the hypoxia mediated vasodilation in animals at rest but hasn’t been shown to be obligatory in humans during acute hypoxia at rest or during exercise.