The evidence has become convincing that in certain critical illnesses such as ARDS, there is pathologic disturbance in O2 delivery to the tissues. This disturbance is marked by an abnormal dependency of O2 uptake upon total O2 delivery. Although this has been attributed to mitochondrial dysfunction in the past, current belief is that such apparent dysfunction is secondary to derangement of the microcirculation that causes an impairment in tissue oxygenation. Microembolization and other disturbances in the local regulation of perfusion have been postulated to be responsible for this derangement. The net effect is to increase the diffusion pathway for oxygen from the tissue capillary. Our ability to deal conceptually with this kind of alteration in tissue oxygenation is dependent upon the mathematical model that is applied. We have discussed two generic models for tissue oxygenation to show the constraints imposed upon quantifying the effects of alteration in any single factor upon tissue PO2. The salient factor that has emerged is that creation of greater than normal heterogeneity in flow or its distribution in the peripheral microcirculation has the inevitable consequence of making tissue hypoxic.