Band 3 and glycophorin A (GPA) are the two most abundant integral proteins of the red cell membrane, being present in approximately 10(6) copies per cell. The main functions of band 3 are membrane anion transport and maintenance of red cell membrane stability through interaction with the cytoskeleton. GPA plays an important role in prevention of red cell aggregation in the circulation and contribution to the glycocalyx. The extracellular domains of both proteins are highly polymorphic. Band 3 carries the antigens (currently 19) of the Diego blood group system and GPA and glycophorin B the antigens (currently 43) of the MNS system. There is substantial evidence that band 3 and GPA associate in the red cell membrane and the Wr(b) antigen, although a product of the band 3 gene, is known to require a complex of GPA and band 3 for normal expression. The discovery of a novel GPA mutation (Ala65-->Pro) giving rise to aberrant Wr(b) expression has been informative with regard to the site of interaction of the two proteins. The extensive array of GPA-related antigens is largely due to genetic events between two closely linked genes and different genetic mechanisms can give rise to the same antigen. This is in contrast to the antigens on band 3 which are exclusively due to single nucleotide mutations in the band 3 gene.