In 2020, three large Phase III Randomized Control Trials (RCTs) that focused on neonatal red blood cell transfusions were published. Two studies evaluated the long term neurocognitive and mortality outcomes of pre-term infants receiving red blood transfusions at high and low hemoglobin thresholds. The third study assessed the use of erythrocyte stimulating agent (erythropoietin) to improve neuroprotection of extremely low birth weight infants (birth weight ≤ 1000 grams). The results of these RCTs will help shape the future of red blood cell transfusion in this highly vulnerable population. This joint AABB/ISBT session will not only discuss the results of these transformative studies but will also explore limitations of these type of trials and the future of optimizing RBC transfusion for these patients. Franz AR, et al. JAMA. 2020;324(6):560-570. Juul SE, et al. N Engl J Med. 2020;382(3):233-243. Juul SE, et al. Jama, Pediatr. 2020;174(10):933-943.