Accurate assessment and treatment of disturbances in oxygenation are crucial to optimal outcomes in critically ill patients. Oxygenation is dependent upon adequate pulmonary gas exchange, oxygen delivery, and oxygen consumption. Each of these physiologic processes may vary independently in response to pathophysiologic conditions and therapeutic interventions. The author reviews diagnostic measures available to evaluate pulmonary gas exchange, oxygen delivery, and oxygen consumption in critically ill patients. Currently available tools and their potential value as well as key methodological limitations are addressed. Failure on behalf of clinicians to fully appreciate these limitations can lead to misdiagnoses and inappropriate treatment. The aim of this article is to help advanced practice nurses more fully understand the implications and limitations of these diagnostic measures to ensure accurate assessment and treatment of disturbances in oxygenation.