Allogeneic barriers to transfusion are caused by differences between those portions of the donor and recipient genomes that define the antigenicity and immune response to the transfused cells. Historically, a blood group antigen was identified when an immune response (alloantibody) was detected by hemagglutination in the serum of a transfused patient. There has been an astounding pace of growth over the past two decades in the field of molecular biology techniques and even more recently in the understanding of the basis of many blood group antigens and phenotypes. Identification of blood group antigens can now be performed in genetic terms, and identification of blood group antibodies can be performed using molecular approaches. This knowledge is being applied to help resolve some long-standing clinical problems that cannot be resolved by classical hemagglutination. This article reviews knowledge of molecular approaches for identifying blood group antigens and antibodies as applied to transfusion medicine practice.