Skeletal muscle blood flow and metabolism are tightly coupled during exercise. Under conditions of strenuous whole-body exercise, there are alterations in the sympathetic and parasympathetic branches of the autonomic nervous system which serve to ensure appropriate perfusion of a large and contracting muscle mass and to also maintain arterial blood pressure. Exercise-induced sympathoexcitation can also result in some vasoconstriction in the contracting musculature. Appropriate blood flow and oxygen delivery are required to sustain muscular contraction and locomotion. It is important to recognize that during exercise, the metabolic demands of both locomotor and respiratory muscles need to be considered where the respiratory musculature is required generate sustained and high levels of force to ensure appropriate levels of ventilation to ensure blood gas homeostasis. As such, the muscles of breathing must receive their ‘fair share’ of cardiac output. It is now well established that performing sustained heavy exercise can result in fatigue in both the limb locomotor and respiratory muscles. In this presentation a summary of the inter-relationships between limb and respiratory muscles during exercise will be made. The case will be made that the evidence to date in humans supports the hypothesis that the high level of sympathetic vasoconstrictor activity emanating from both limb and respiratory muscle metaboreceptors in heavy intensity exercise constrains blood flow and O2transport, thereby promoting both diaphragm and locomotor muscle fatigue during whole body exercise at high intensity. Emphasis will be given to newer studies that experimentally manipulate respiratory muscle work to evaluate muscular fatigue and blood flow distribution (1).