Clinically useful indicators of physiologically significant anemia requiring intervention have yet to be defined in the newborn. Finding a simple noninvasive marker of physiologically significant anemia remains elusive but is a laudable goal considering the risks of transfusion therapy and requirement for repeated parenteral (subcutaneous or IV) administration or r-HuEPO, when chosen as a preventive or therapeutic option. The asymptomatic newborn has shown considerable tolerance to anemia without detrimental effects and need for an iatrogenic increase in RBC mass. Newer guidelines for transfusion are emerging that lower the threshold hematocrit and hemoglobin concentration at which RBC transfusion may be considered. Following those guidelines alone may decrease the need for transfusion and improve our understanding of the physiologic impact of anemia in the neonate. Ongoing investigation in understanding better the physiologic impact and consequences of anemia is critical in that regard.