Rh hemolytic disease (HDN) is the prototype of maternal alloimmunization and fetal hemolytic disease. There are other antigens capable of causing alloimmunization and hemolytic disease such as c, Kell, and Fya. Rh immunization is usually caused by a prior Rh positive fetal maternal transplacental hemorrhage, which occurs in at least 75% of pregnancies. Unless treated, hemolytic disease will result in kernicterus or fetal hydrops in 25% of cases, respectively. Neonatal exchange transfusion has eradicated kernicterus. Measures available to predict severity of fetal hemolytic disease are maternal antibody titers, prior history of hemolytic disease, in vitro cell-mediated maternal antibody functional assays, amniotic fluid spectrophotometry, ultrasound fetal assessment, and fetal blood sampling. The Rh or Kell antigen status of the fetus may be determined by amniotic fluid PCR testing. The management of the severely affected fetus consists of early delivery, with or without fetal transfusions, depending on the gestation of the fetus. With the use of these diagnostic and treatment measures, perinatal mortality from hemolytic disease of the fetus and newborn has been reduced in Manitoba, population one million, from 100 per year in the early 1940s to 1 every 3 years in the mid 1990s.