Our understanding of acute hypoxemic respiratory failure has evolved continually over the past 100 years. Currently, much attention is focused on the peripheral consequences of the adult respiratory distress syndrome, because the systemic sequelae are a significant contributor to morbidity and death from the condition. The unexpected relation between O2 supply and uptake in the periphery of these patients could be a signal of occult tissue hypoxia. If so, this would have important implications for clinical care aimed at minimizing the multiple system organ failure that often develops. Alternatively, the increases in uptake seen when delivery is increased could arise in part from coupling error, uptake by nonmitochondrial oxidase systems, oxygen radical formation, and the normal increases in uptake seen in the range of relative O2 supply independence. Future evolution in our understanding of ARDS will require a careful evaluation of the adequacy of tissue oxygenation and the role of tissue hypoxia in this syndrome. Promising new approaches such as near-infrared spectroscopy and magnetic resonance imaging may help provide indices of tissue O2 supply limitation that complement regional measurements of tissue function.