Evaluation of hemolytic anemia in the newborn may be complicated owing to the physiologic changes that occur during this time; however, the newborn period is a time when congenital red cell abnormalities may first present and when maternal factors need to be considered. In this article, an approach to the diagnosis of hemolytic disease in the newborn is reviewed. The unique properties of the neonatal red cell, the normal red cell changes present in the neonate, the potential congenital defects and maternal factors that may influence the associated clinical and laboratory findings consistent with the diagnosis of hemolytic anemia, and a brief review of the red cell disorders associated with hemolytic anemia in the newborn are discussed.