After completing this article, readers should be able to: 1. Compare and contrast the safety and efficacy of donor red blood cell transfusions and transfusion-sparing approaches. 2. Describe the potential advantages of point-of-care testing and in-line monitors in the neonatal intensive care unit. 3. Delineate the benefits of recombinant erythropoietin for the treatment of neonatal anemia. 4. Describe the benefits of adopting transfusion guidelines in the neonatal intensive care unit. 5. Delineate the role of autologous placental blood in newborns. In the past 15 years, adoption of strategies to minimize allogeneic blood transfusions has changed the epidemiology of blood usage in the neonatal intensive care unit (NICU). More infants remain free of transfusions, and significantly fewer transfusions are administered during hospitalization. These changes are particularly striking when taking into account the increased survival of smaller and sicker neonates and are attributable, in part, to re-evaluation of indications for transfusions (stricter transfusion guidelines), more discriminate laboratory testing, and administration of recombinant erythropoietin (r-EPO). These strategies have not been accepted universally because of issues of short- and long-term risk, cost, and benefit. These issues are particularly relevant because the safety of the blood supply has increased dramatically during the same 15 years. This review presents an overview of current trends and future prospects of traditional and nontraditional strategies to minimize red blood cell transfusion. The risks of transfusion-transmitted viral infections currently are so low that mathematical models are necessary for estimation. Patients who have transfusion-transmitted hepatitis and human immunodeficiency virus (HIV) are reported so rarely that possible transmission rates must be estimated by donor seroconversion rates, donation frequency, and other indirect factors. For example, the risk of acquiring HIV dropped 10,000-fold from 1983 to 1996 and is certain to fall even further, perhaps to zero risk, with implementation of nucleic acid amplification testing of donor blood. The …