Liberal versus restrictive red blood cell (RBC) transfusion triggers have been debated for years. This review illustrates the human body's physiologic response to acute anemia and summarizes the evidence from prospective randomized trials (RCTs) for restrictive use of RBC transfusions in high-risk patients. During progressive anemia, the human body maintains the oxygen delivery to the tissues by an increase in cardiac output and peripheral oxygen extraction. Seven RCTs with a total of 5,566 high-risk patients compared a restrictive hemoglobin (Hb) transfusion trigger (Hb < 70 or < 80 g/l) with a liberal Hb transfusion trigger (Hb < 90 or < 100 g/l). Unanimously these studies show non-inferiority, safety, and a significant reduction in RBC transfusions in the restrictive groups. In one RCT mortality was higher in the liberal Hb transfusion group, and in two additional RCTs mortality of subgroups or after risk adjustment was significantly higher in the liberal Hb transfusion trigger groups. Conclusion: Strong RCT evidence suggests the safety of restrictive transfusion triggers. As a consequence, an Hb transfusion trigger of <70 g/l is recommended for high risk patients.