Pathologic oxygen supply dependency is an abnormal situation in which oxygen uptake (Vo2) varies directly with oxygen delivery. Its presence in patients with adult respiratory distress syndrome and/or sepsis has been associated with particularly high mortality rates that may be the result of tissue hypoxia that causes multiple organ failure. The evidence for this association has been indirect because we cannot use invasive methods that would be necessary to verify or disprove the hypothesis. Because further progress will depend on the development of adequate animal models of pathologic oxygen supply dependency, we have attempted to evaluate some of the available information in this area as well as the likelihood that tissue hypoxia will prove to be the precipitating factor. In anesthetized dogs injected or infused with endotoxin, many of the features of pathologic oxygen supply dependency have been successfully produced. These features include defective peripheral oxygen extraction, increased oxygen demand, and increased lactate levels. Regional measurements have shown that gut Vo2 decreases before other areas, particularly skeletal muscle. Lactate measurements alone were shown not to be sufficient proof of tissue hypoxia. More direct measurements of actual energy states and tissue Po2 are indicated for future research efforts.