The adequacy of tissue oxygenation depends on the interaction of many factors. Assuming the presence of sufficient tissue perfusion, oxygenation failure must be caused by depressed respiratory efficiency (shunt or other ventilation/perfusion mismatch), inadequate FIO2/PaO2 relationships (alveolar-capillary diffusion deficits, for example), or oxygen transport difficulties (hemoglobin loading/unloading dysfunction). When presented with patients whose respiratory distress is not alleviated by application of increasing levels of FIO2 and seemingly adequate SaO2 values, one must look toward less obvious reasons for the disparity between subjective and objective findings. Early response by clinicians to situations such as those just mentioned should include a survey and analysis of hemoglobin status. It is important to note that meaningful co-oximetry results depend on the quality of the patient history and other laboratory tests to rule out factors that might affect the co-oximetry results. Good preparation of the sample is essential to ensure that adequate hemolysis has occurred and that the sample was not contaminated prior to analysis. A well designed and executed program of preventive maintenance and QA is important. It should include preparation and sampling as well as technique and instrument integrity. All of these are essential for safe, effective, and accurate determination and dissemination of this important clinical information.