The lungs, airways and respiratory muscles of healthy humans are typically considered ‘overbuilt’ for the ventilatory and gas-exchange demands imposed by exercise. However, respiratory disease can compromise oxygen (O2) delivery to the locomotor muscles and cause premature peripheral muscle fatigue during exercise. Cystic fibrosis (CF) is an autosomal recessive condition caused by mutations to the CF transmembrane conductance regulator (CFTR) gene. CF is traditionally associated with chronic respiratory infections and the development of bronchiectasis, resulting in respiratory failure, hypoxaemia and hypoventilation. However, CFTR protein is expressed in multiple organs and, thus, this complex condition can pose significant alterations to central and localised O2 delivery, as well as the ability to effectively extract and utilise O2 at the myocyte level, even when pulmonary function is preserved. Understanding the mechanisms that can limit the ability to exercise in people with CF is important, as aerobic exercise function is linked to quality of life, risk of being hospitalised with pulmonary exacerbation and, ultimately, prognosis. Since intense exercise poses considerable challenge to arterial O2 content and/or blood flow and its distribution to the working skeletal muscle, evaluating the exercise physiology of people with CF has helped us elucidate potential underlying mechanisms by which the disease can limit exercise performance. Experimental manipulations that would enhance O2 delivery to the locomotor muscle in healthy individuals have also offered insight into the putative mediators of aerobic exercise (dys)function in this population. In healthy individuals, skeletal muscle blood flow and metabolism are tightly coupled. However, aerobic exercise function and, more specifically, skeletal muscle oxidative metabolism can be limited by central and peripheral factors in chronic disease states. This talk will provide a contemporary overview of the central and peripheral contributors of CF pathophysiology that modulate the dynamic balance between O2 delivery-to-utilisation during exercise. The case will be made that at the mild end of the CF disease spectrum, the human body has the ability to physiologically compensate for some degree of dysfunction, in an effort to maintain the metabolic demands of lower intensity exercise. However, with more severe dysfunction, a pharmalogical ‘helping hand’ may be needed to improve exercise capacity and, thus, quality of life.