Platelet transfusions were introduced into clinical medicine about 60 years ago when they were shown to reduce the mortality rate of patients with leukemia who were bleeding secondary to hyporegenerative thrombocytopenia. In modern neonatology units, platelet transfusions are integral and indeed lifesaving for some neonates. However, the great majority of platelet transfusions currently administered in neonatal intensive care units (NICUs) are not given in the original paradigm to treat thrombocytopenic hemorrhage, but instead are administered prophylactically with the hope that they will reduce the risk of spontaneous bleeding. Weighing the risks and benefits of platelet transfusion, although imprecise, should be attempted each time a platelet transfusion is ordered. Adopting guidelines specific for platelet transfusion will improve consistency of care and will also generally reduce transfusion usage, thereby reducing costs and conserving valuable blood bank resources. Initiating specific programs to improve compliance with transfusion guidelines can further improve NICU transfusion practice.