Lung metabolism has been extremely difficult to determine in vivo primarily because the lung is overwhelmed by a great blood flow that generally makes the Fick principle inadequate. Largely for reasons such as this, investigators have had to rely on in vitro preparations. The isolated perfused lung has the apparent advantage of being similar to the lung in vivo when compared with other preparations. For instance, there is evidence that the capillary bed of the lung may alter substrates and influence their subsequent metabolism. Substrates have contact with the capillary endothelium in isolated perfused lungs but not to tissue slices, homogenates, or isolated cells. Our studies indicate that precursors of saturated phosphatidylcholine may include lipids, which are hydrolyzed in the capillary of the isolated perfused lung and thus become substrates such as free fatty acids, etc. However, tissue slices do not use the esterified lipids to the same extent, presumably because in this preparation the enzymes in the capillary endothelium do not have contact with the esterified lipids. Substrate utilization of the isolated perfused lung may be considerably altered by inflation of the lung or by pulmonary edema. Although glucose utilization and palmitate oxidation by the isolated perfused lung and by tissue slices of the rat lung are very similar, if the isolated perfused lung develops pulmonary edema, glucose utilization increases by nearly 100%. This phenomenon is apparently not due solely to fluid in the airspaces because in control studies with fluid added into the airways the glucose utilization did not increase to the degree observed with edematous lungs. Lung distention is associated with increased glucose consumption but marked distention is also associated with pulmonary edema. The effect of lung distension may be a direct effect or it may be secondary to the pulmonary edema.