Hemolytic disease of the fetus and newborn (HDFN) is an important condition to recognize, as preventative and treatment strategies are available to circumvent morbidity and mortality. Signs and symptoms of HDFN can range from self-limited hemolytic anemia to life-threatening hydrops fetalis. Incompatibility in both major and minor blood groups can lead to HDFN, as maternal immunoglobulin G (IgG) alloantibodies against fetal erythrocyte antigens that are not expressed in the mother can cross the placenta and cause destruction of fetal and newborn erythrocytes. Antenatally, performing maternal blood typing and antibody screening and administering anti-RhD intravenous immunoglobulin to RhD negative mothers can prevent RhD hemolytic disease. Postnatally, close monitoring of the newborn for pathologic hyperbilirubinemia and performing direct antiglobulin testing can identify newborns at risk of HDFN. Treatments such as phototherapy, intravenous immunoglobulin (IVIG), and exchange red blood cell transfusions may be clinically indicated in some situations, and infants should be monitored for late anemia.