The RBC Rh antigens are of large clinical importance, but until recently have been poorly understood at a molecular level. The Rh polypeptides are a family of nonglycosylated Mr 30- to 32-Kd transmembrane proteins that are core structural components of the Rh antigens and have been purified and partially characterized biochemically. Rh polypeptides are present in RBCs from normal humans and other mammalian species and are probably required for normal membrane integrity, because they appear to be missing from the RBCs of the rare Rhnull individuals that express several membrane defects. The Rh polypeptides contain an exofacial free sulfhydryl that is important for Rh antigenic reactivity and several intracellular sulfhydryls that appear to be palmitylated, but most of the molecule appears to reside between the leaflets of the phospholipid bilayer. The cDNA coding for a 416-amino acid Rh polypeptide was recently isolated but was not found to share sequence homology with any known protein, and Northern analysis indicated that Rh is erythroid specific. The Rh antigens within the native membranes are thought to exist as a complex of Rh polypeptides and multiple other membrane components, including certain Rh-related glycoproteins. While it is thought that this assembly may be important for the Rh antigenic reactivity, the structural basis of this remains to be established. While the physiologic role of Rh is yet to be defined, several clues indicate that it may play a role in the organization of membrane phospholipids or synthesis or membrane expression of various glycoproteins. While our knowledge of Rh is still very incomplete, recent research has significantly advanced the molecular understanding of these important blood group antigens.