Anemia and red blood cell transfusion are associated with adverse outcomes. Large randomized trials have demonstrated that restrictive transfusion strategies can safely reduce patient exposure to transfusion, forming a foundational pillar of patient blood management. The restrictive transfusion thresholds in these trials ranged from 7 to 8 g/dL for different populations and this variability is reflected in recent guideline recommendations for transfusion triggers. Such variability implies heterogeneity among populations with respect to the transfusion threshold for optimal outcomes. Individual variability (tolerance to anemia, risk of tissue hypoxia, risk of red blood cell transfusion) has not been addressed by population-based trials, supporting the argument for ‘physiological transfusion triggers’ indicative of inadequate organ perfusion. However, physiological triggers have only been assessed in small feasibility trials without convincing outcome data. This review summarizes data from recent transfusion trials and transfusion guidelines, and reviews potential physiological triggers which could further refine transfusion practices and minimize risks of tissue hypoxia and adverse outcomes.