Resolving the bases for different physiological functioning or exercise performance within a population is dependent on our understanding of control mechanisms. For example, when most young healthy individuals run or cycle at moderate intensities, oxygen uptake (VO2) kinetics are rapid and the amplitude of the VO2 response is not constrained by O-2 delivery. For this to occur, muscle O-2 delivery (i.e., blood flow x arterial O-2 concentration) must be coordinated superbly with muscle O-2 requirements (VO2), the efficacy of which may differ among muscles and distinct fiber types. When the O-2 transport system succumbs to the predations of aging or disease (emphysema, heart failure, and type 2 diabetes), muscle O-2 delivery and O-2 delivery-VO2 matching and, therefore, muscle contractile function become impaired. This forces greater influence of the upstream O-2 transport pathway on muscle aerobic energy production, and the O-2 delivery-VO2 relationship(s) assumes increased importance. This review is the first of its kind to bring a broad range of available techniques, mostly state of the art, including computer modeling, radiolabeled microspheres, positron emission tomography, magnetic resonance imaging, near-infrared spectroscopy, and phosphorescence quenching to resolve the O-2 delivery-VO2 relationships and inherent heterogeneities at the whole body, interorgan, muscular, intramuscular, and microvascular/myocyte levels. Emphasis is placed on the following: 1) intact humans and animals as these provide the platform essential for framing and interpreting subsequent investigations, 2) contemporary findings using novel technological approaches to elucidate O-2 delivery-VO2 heterogeneities in humans, and 3) future directions for investigating how normal physiological responses can be explained by O-2 delivery-VO2 heterogeneities and the impact of aging/disease on these processes.