Publisher Summary This chapter focuses on the Rh blood group system and this system is second to the ABO system in clinical importance because of the Rh antigens. The Rh antigens are highly immunogenic and the corresponding antibodies can result in hemolytic transfusion reactions and hemolytic disease of the fetus and newborn. The Rh system has at least 45 antigens, which are carried on the RhCE protein encoded by the RHCE gene and the D antigen on the RhD protein encoded by the RHD gene. A table is presented that illustrated the nomenclature and prevalence of Rh haplotypes. The presence or absence of the D antigen confers the Rh-positive or Rh-negative status and in the US, 85% of the general population are D positive (Rh positive) and 15% are D negative (Rh negative). Weak D is the term applied to RBCs that carry weak (low antigen concentration) forms of D and it cannot be detected using direct agglutination with anti-D reagents at room temperature. Another form is called partial D, in which the individual lack a portion of the D protein and when exposed to the D antigen or transfused RBCs can produce alloantibodies to the missing portion of D.