Hemoglobin-based red blood cell transfusion (RBC) triggers do not clearly identify which patients with moderate anemia (hemoglobin 7-10 g/dL) will benefit from RBC transfusion. The National Heart, Lung, and Blood Institute has recognized the need for bedside oxygenation measures to enhance transfusion decision-making. This narrative review uses four studies to explore the potential of the oxygen extraction ratio (O2ER)-the ratio of consumed oxygen to delivered oxygen in a critical tissue bed as a more physiologically relevant indicator for guiding RBC transfusions in patients with moderate anemia. The aim of this review is to present existing data on the relationship between O2ER and responsiveness to RBC transfusion, as well as the feasibility of O2ER as bedside measure of tissue oxygenation. This review presents a narrative appraisal of three critical papers that investigate the relationship between O2ER and transfusion outcomes, and one paper that demonstrates proof-of-concept for a noninvasive device to measure O2ER at the bedside. Despite limitations in the existing studies, including small sample sizes and observational designs, the evidence collectively suggests that O2ER has the potential to enhance transfusion decision accuracy. The development of noninvasive measurement devices could facilitate widespread implementation in many kinds of care settings.