In 1968, Saltin et al. published a landmark paper describing the alterations in VO2max resulting from two sequential interventions – 20 days of bed rest and almost 8 weeks of training. They concluded that bed rest reduced VO2max through reductions in maximal cardiac output, while training enhanced VO2max by an equal combination of increased maximal cardiac output and increased arterio-venous [O2] difference (A-V Δ [O2]). At the time, A-V Δ [O2] was taken as an index of peripheral (skeletal muscle) adaptation. A key interpretive element that was not featured was consideration of how alterations in cardiac output affect the O2 extraction process secondary to changes in red cell transit time through the muscle microcirculation, even in the absence of adaptive changes in the skeletal muscles per se. For the 2015 Saltin Symposium, it was therefore thought appropriate to re-examine the 1968 O2 transport data and re-evaluate the roles central cardiovascular and peripheral muscle changes after bed rest and training allowing for their interaction. The analysis supports the conclusion that bed rest reduced VO2max mainly through reduction in cardiac output, but after training, it is proposed that the 1968 conclusions should be modified: the majority of the increase in VO2max from the control state can be attributed to an improvement in diffusive unloading of O2 from the muscle microcirculation, with a much smaller role for enhanced blood flow.