Prior to the 1970s and the advent of Rho (D) immune globulin (RIG) for Rh negative women, hemolytic disease of the newborn led to morbidity, long-term disabilities, and mortality. Antepartum RIG administration has been a standard of practice since 1983. Yet, Rh isoimmunization (sensitization) and its sequelae have not been completely eradicated. Rh-related issues remain clinical challenges facing perinatal and neonatal nurses. Evidence for the administration of RIG prenatally and during the postpartum period is presented including controversies and challenges. Current information about fetal and neonatal care of erythroblastosis fetalis and immune hydrops is also presented.