Many controversial questions regarding the practice of neonatal red blood cell (RBC) transfusions exist, so that practices and policies vary widely. This article will critically assess information pertaining to two of these controversies, namely, the transfusion of RBCs stored for up to 42 days after collection vs the transfusion of fresh RBCs stored 7 days or less after donation and the use of recombinant human erythropoietin (rHuEPO) in attempts to either diminish the severity of or to treat the anemia of prematurity. Based on both theoretical considerations and several published clinical trials, RBCs from one donor stored up to 42 days in extended storage preservative solutions can safely provide all RBCs needed by most infants for small-volume transfusions. Based on a large number of clinical trials and a meta-analysis of these trials, it is impossible to provide firm guidelines for the use of rHuEPO in the treatment of the anemia of prematurity. Clearly, rHuEPO has efficacy in stimulating erythropoiesis in preterm infants, but success in the elimination or marked reduction in the need for RBC transfusions has not been definitively demonstrated.