In recent years technologic advances have led to the understanding of the molecular genetics of many blood group antigens. This review highlights the molecular basis of selected antigens and describes implications for transfusion medicine. The knowledge can be used in the following clinical settings to genotype a patient: 1) to identify a fetus at risk for hemolytic disease of the newborn 2) to genotype patients who have been recently transfused or whose erythrocytes have a positive direct antiglobulin test 3) to determine which phenotypically Fy(b-) patients have the FY*B gene, 4) to genotype when an antigen has a depressed expression on erythrocytes, 5) to mass screen for anitgen-negative donors, 6) to resolve blood group A, B, and D typing discrepancies, 7) to determine the zygosity of RhD, 8) to determine the origin of engrafted leukocytes in a stem cell recipient, 9) to determine the origin of lymphocytes in a patient with graft-versus-disease, 10) for tissue typing, 11) for paternity testing, and 12) for forensic testing.