Alloantibodies to blood group antigens are produced because there are differences between the blood group antigens on recipient and donor (or mother and fetus) red blood cells. Historically and currently, blood group antibodies and antigens are detected by hemagglutination, which can require considerable skill. Over the past 2 decades, there has been an astounding pace of growth in the field of molecular biology techniques and even more recently in the understanding of the basis of many blood group antigens and phenotypes. Thus, we are now able to consider identification of blood group antigens in genetic terms and identification of blood group antibodies using molecular approaches. Indeed, this knowledge is being applied to help resolve some long-standing clinical problems that cannot be resolved by classic hemagglutination. This article reviews our current knowledge of molecular approaches for identifying blood group antigens and antibodies as applied to transfusion medicine.