Appropriate cardiovascular and hemodynamic adjustments are necessary to meet the metabolic demands of working skeletal muscle during exercise. Alterations in the sympathetic and parasympathetic branches of the autonomic nervous system are fundamental in ensuring these adjustments are adequately made. Several neural mechanisms are responsible for the changes in autonomic activity with exercise and through complex interactions, contribute to the cardiovascular and hemodynamic changes in an intensity-dependent manner. This short review is from a presentation made at the Saltin Symposium June 2–4, 2015 in Copenhagen, Denmark. As such, the focus will be on reflex control of the circulation with an emphasis on the work of the late Dr. Bengt Saltin. Moreover, a concerted effort is made to highlight the novel and insightful concepts put forth by Dr. Saltin in his last published review article on the regulation of skeletal muscle blood flow in humans. Thus, the multiple roles played by adenosine triphosphate (ATP) including its ability to induce vasodilatation, override sympathetic vasoconstriction and stimulate skeletal muscle afferents (exercise pressor reflex) are discussed and a conceptual framework is set suggesting a major role of ATP in blood flow regulation during exercise.