The regulation of skeletal muscle blood flow and oxygen delivery to contracting skeletal muscle is complex and involves the mechanical effects of muscle contraction, local metabolic and endothelial-derived substances, and the sympathetic nervous system (SNS). With advancing age in humans, skeletal muscle blood flow is reduced during dynamic exercise and this is due to a lower vascular conductance, which could ultimately contribute to age-associated reductions in aerobic exercise capacity, a primary predictor of mortality in both healthy and diseased ageing populations. Recent advances in our understanding of vascular control during exercise in older humans indicate that the normal contribution of endothelium-derived substances (e.g. nitric oxide and prostaglandins) is impaired with age as would be predicted by age-related endothelial dysfunction. Additionally, evidence from our laboratory and others indicate that the ability to limit SNS-mediated vasoconstriction (“functional sympatholysis”) is also impaired with advancing age, which could further reduce skeletal muscle perfusion during high intensity and/or large muscle mass exercise. Most recently, our laboratory has demonstrated that intravascular adenosine triphosphate (ATP) draining active skeletal muscle does not significantly increase during exercise in older adults, and given the dual vasoactive nature of ATP in the human circulation, could potentially explain impaired local vasodilatation and impaired functional sympatholysis with advancing age in humans.