Blood group antigens reside on cell surface molecules of wide structural and functional diversity. Although all are serologically detectable on red blood cells, most are also expressed in non erythroid tissues, but with a few exceptions their biological role on erythrocytes and tissues often remains elusive. Deficiencies of these molecules seen either in rare blood group "null" phenotypes and/or associated with red cell membrane disorders, offer the opportunity to clarify their role in the cell membrane and to correlate their molecular abnormalities with cell dysfunctions. This review will summarize some of the present knowledge on these defects and on gene targeting studies developed to analyze the function of these molecules in animal models.