Gas exchange in any tissue or organ requires O 2 delivery (and CO 2 removal) along a transport pathway involving, sequentially, the lungs, heart, blood, circulation, and tissues. Convective factors governed mostly by the lungs, heart, blood, and circulation determine how much O 2 reaches each tissue, while diffusion underlies tissue O 2 unloading and transport to mitochondria. O 2 consumption may be limited by these transport processes, or alternatively may be set by tissue metabolic demand. The maximal amount of O 2 available to mitochondria is not determined uniquely by any one step in the transport pathway, but by all in an integrated manner. Because the pathway steps are arranged in series, poor function of any single step significantly reduces maximal O 2 transport, while greater than normal function of any such step increases overall transport only slightly. When considering central and peripheral limitations to O 2 transport, it is evident that convective O 2 delivery to tissues depends in part on peripheral factors (regional vascular conductances), while diffusive unloading in the periphery depends in part on central factors (especially blood flow). In both health and disease, central and peripheral factors contribute to limitations on O 2 transport, at least in the area of muscle function during exercise, where the O 2 transport system is often stretched to its limits.