In recent years, advances in biochemistry and molecular genetics have contributed to establishing the structure of the genes and proteins from most of the 23 blood group systems presently known. Current investigations are focusing on genetic polymorphism analysis, tissue-specific expression, biological properties and structure-function relationships. On the basis of this information, the blood group antigens were tentatively classified into five functional categories: (i) transporters and channels, (ii) receptors for exogenous ligands, viruses, bacteria and parasites, (iii) adhesion molecules, (iv) enzymes and, (v) structural proteins. This review will focus on selected blood groups systems (RH, JK, FY, LU, LW, KEL and XK) which are representative of these classes of molecules, in order to illustrate how these studies may bring new information on common and variant phenotypes and for understanding both the mechanisms of tissue specific expression and the potential function of these antigens, particularly those expressed in nonerythroid lineage.