Blood group genotyping using DNA extracted from fetal tissue is useful to identify fetuses at risk for hemolytic disease of the fetus and newborn (HDFN) due to maternal red cell alloantibodies. Four considerations are important for fetal blood group genotyping. First, paternal heterozygosity must be established, including tests that evaluate RHD hemizygosity. Second, the source of fetal tissue for DNA extraction requires certain considerations. Third, because the fetal genotype is used to predict the expressed phenotype, a thorough knowledge of blood group genetics is required. Moreover, the test algorithm should include the evaluation of the parental phenotypes and genotypes to help identify variant alleles. Fourth, the blood group antigen expression at birth should be evaluated to confirm the inheritance. The identification of an antigen-negative fetus on the basis of the blood group genotype provides significant advantages in managing the pregnancy at risk for HDFN. In the near future, fetal DNA in maternal plasma will likely replace fetal blood group genotyping for RHD. Significant challenges remain to detect other clinically significant blood group antigens using maternal plasma DNA.