Complex physiologic interactions exist between oxygenation, hemoglobin, and cardiac output (Qt) in critically ill patients with respiratory failure. When any or all of these three critical factors fail, clinicians are challenged to support oxygen delivery (DO(2)) in order to avoid tissue hypoxia, end-organ damage, and high mortality rates. Many of the interventions performed to improve DO(2), including mechanical ventilation, blood transfusions, fluid management, and invasive monitoring of cardiac function, are accompanied by serious risks that can exacerbate the pathology of DO(2). This article provides an overview of oxygenation, hemoglobin, and Qt in patients with respiratory failure and highlights some of the current research that seeks safe and effective ways to improve DO(2) in these patients.