The pulmonary vascular endothelium, a metabolically active tissue, serves as an important site of injury in many types of clinical and experimental lung disease. Removal of 5-HT from the circulation constitutes one of the endothelial metabolic functions that is depressed early in the course of lung injury. Experimental evidence confirms that measuring 5-HT uptake detects alterations in endothelial cell function that precede the abnormalities detected by more conventional diagnostic tests such as radiographs, pulmonary function tests, and arterial blood gases. In addition, depression of 5-HT uptake can lead to increased concentrations of 5-HT in the pulmonary vasculature, which may contribute to the pathogenesis of lung injury. The development of an ideal method for measuring 5-HT uptake accurately in the lungs of critically ill patients has just begun. As yet, numerous variables reviewed in this article confound clinical measurements of 5-HT uptake. However, if investigators can continue to refine and develop the techniques for measuring 5-HT uptake in human patients, clinicians can look forward to the addition of a sensitive tool to their diagnostic armamentarium. Hopefully, the ability to detect diffuse lung injury earlier in its course will enable future clinicians to institute therapy that will prevent the pathologic progression to morbidity and death seen all too frequently in current medical practice.