Rh is the most complex of the blood groups systems, embracing over 45 distinct antigens, the absence or presence of which combine to exhibit an individual's Rh blood group type. The most clinical important antigen, D or Rh_o, was the first discovered in 1940 and has been generally referred to as the Rh antigen, being present in over 85% of the random population. Those individuals that lack the D antigen are considered to be Rh negative.

The Rh antigens are encoded by two highly homologous and closely linked genes on the short arm of chromosome 1. The RHD gene producing the D antigen, or most of its components; RhCE gene producing the Cc and Ee antigens or their variants. The majority of the antigens within this system represent products of gene cross-over, point mutations or deletions within one or both genes.

The Rh antigens appear to be red cell specific, appearing early during development of red blood cells, and have not been found on other body tissues. Antibodies against the Rh antigens have caused severe and fatal transfusion reactions and hemolytic disease of the newborn. The importance of the Rh antigens in the erythroid membrane is exemplified by the fact that in many examples of auto-immune hemolytic anemia, auto-Rh antibodies are frequently found.

Moreover, in hematological testing the extremely rare (only 32 known throughout the world) individuals who have no detectable Rh antigens, Rh_null individuals, a shortened red cell survival is quite common. Rh_null cells exhibit stomatocytosis and spherocytosis, and have increased permeability to potassium suggesting that they lack a crucial membrane component. A current model suggests that Rh assembles in the membrane as a complex with CD47, LW, RhAG and glycophorin B. Mutations of the RhAG gene accounts for most examples of Rh_null

It is truly ironic that this blood group system received this name because it was originally thought to be similar to an antibody produced in rabbits that had been immunized with rhesus monkey cells. By the time it was scientifically proven that they were two distinct antibody specificities there were too many publications referring to the Rh factor as the product of the D gene and the symbol Rh was well entrenched for this blood group system. Hence, the rhesus association to the system name had been made, but in fact, there is no association with rhesus monkeys what so ever. That antibody produced in rabbits to rhesus monkey cells, and the similar human antibody specificities, have been named after the two original investigators, Landsteiner and Wiener (refer to LW blood group system).