Since the 1950s, neonatal intensive care practitioners have worked to preserve brain oxygenation. The physiological rationale that red blood cell (RBC) transfusion improved oxygen carrying capacity was a tantalizing prospect. In this issue of JAMA Pediatrics, Saito-Benz et al1 renew such hopes in a novel proof-of-concept randomized clinical trial (RCT) of irradiating RBCs on the day of transfusion (which the authors termed fresh irradiation) to boost cerebral oxygen saturation. Their PICOT (population/patient, intervention, comparison, outcome, and time) question was whether stable very low-birth-weight preterm infants requiring a top-up transfusion who received freshly irradiated RBCs showed an improvement in the noninvasively measured brain oxygenation compared to those who received routinely irradiated RBCs in a neonatal intensive care unit with high transfusion thresholds.