Systemic hypoxia is sensed by carotid chemoreceptors, which evoke a complex pattern of reflex responses that includes hyperventilation, tachycardia and generalised increase in sympathetic vasoconstrictor activity. The hyperventilation and tachycardia wane due to local influences of hypoxia that include the actions of adenosine. Further, in skeletal muscle, the sympathetic vasoconstriction is overcome by vasodilatation, which arises in large part because endothelial cells “sense” falls in O2 concentration. Thus, NO that is generated tonically by shear stress competes with O2 for the same binding site on endothelial cytochrome oxidase raising its Km, such that even moderate falls in O2 decrease ATP synthesis. Our evidence indicates this leads either directly to adenosine release from endothelial cells, or to adenosine being generated extracellularly from lower adenine nucleotides. Adenosine then acts on endothelial A1 receptors to release NO and cause muscle vasodilatation via a pathway that involves synthesis of PGI2 as an intermediate. Acute hypoxia also leads to generation of reactive oxygen species (ROS) in skeletal muscle. Since xanthine oxidase inhibition attenuates hypoxia-induced dilatation, while exogenous superoxide dismutase (SOD) potentiates it, we have proposed that H2O2 generated from O2-, partly as a consequence of adenosine metabolism, contributes to the vasodilatation. The effects of chronic systemic hypoxia depend critically on stage of development. In adult rats exposed to chronic hypoxia (CH), adenosine exerts a tonic dilator influence on skeletal muscle via A1 receptors and NO, which is resolved by day 7 when haematocrit is increasing. Moreover, on days 1-7 and at 3-5 weeks of chronic hypoxia, the adenosine-mediated dilator influence of acute hypoxia is accentuated, suggesting the endothelial “NO-adenosine sensing” mechanism is up-regulated in CH rats. By contrast, rats exposed to chronic hypoxia from birth for 6-7 weeks (CHB), show more pronounced secondary waning of ventilation and heart rate than controls in acute hypoxia, such that arterial pressure falls more profoundly and cerebral blood flow falls. Moreover, whilst their secondary hypoventilation and bradycardia are attributable to adenosine, the muscle vasodilatation is not mediated by adenosine. On the other hand, rats that are exposed to chronic hypoxia in utero, but reared in air (CHU), show no exacerbation of the secondary hypoventilation and bradycardia in acute hypoxia, but again their substantial muscle vasodilator response is not mediated by adenosine even though it is NO-dependent. Thus, the endothelial “NO-adenosine sensing” mechanism is apparently disturbed in CHB and CHU rats. Our recent findings suggest that differences in oxidant status may play a critical role in determining the long-term cardiovascular consequences of chronic hypoxia at different stages of development.