Red blood cell and blood product transfusion in the fetus, neonate, and premature infant are often administered with poorly defined indications and unintentional adverse consequences. Products may be altered in an effort to limit potential adverse events or may be specially selected to meet the unique needs of a specific diagnosis. One area of particular concern to neonatologists is selection blood for small volume (5-15 mL/kg) transfusions in premature infants. For infants, use of red blood cells collected in anticoagulant-additive solutions and administered in small aliquots over the shelf life of the product to decrease donor exposure has supplanted the use of fresh red blood cells with each transfusion resulting in a donor exposure. The safety of this practice has been documented and procedures established to aid a transfusion service in making these products available. Less well established are the indications for transfusion in this population; hemoglobin or Hematocrit alone are likely insufficient unless clinical findings like oxygen desaturation, apnea, and bradycardia are part of the criteria used to define transfusion need. The comorbidities that increase oxygen demands in these infants, like bronchopulmonary dysplasia and increased oxygen consumption to accommodate growth, must be part of the decision to transfuse. Noninvasive methods or assays that will reflect the unique pathophysiology of oxygen delivery and peripheral oxygen offloading are needed.