Skeletal muscle and cardiovascular system responses to exercise are so closely entwined that it is often difficult to determine the effector from the affector. The purpose of this manuscript and its companion papers is to highlight (and perhaps assist in unraveling) the interdependency between skeletal muscle and the cardiovascular system in both chronic and acute exercise. Specifically, we elucidate four main areas: 1) how a finite cardiac output is allocated to a large and demanding mass of skeletal muscle, 2) whether maximal muscle oxygen uptake is determined peripherally or centrally, 3) whether blood flow or muscle metabolism set the kinetic response to the start of exercise, and 4) the matching of structural adaptations in muscle and the microcirculation in response to exercise. This manuscript, the product of an American College of Sports Medicine Symposium, unites the thoughts and findings of four researchers, each with different interests and perspectives, but with the common intent to better understand the interaction between oxygen supply and metabolic demand during exercise.