© 2018 Elsevier Inc. All rights reserved. Blood groups can be divided into those consisting of carbohydrate antigens and those that are protein in nature. Carbohydrate blood group systems include ABO, H, Lewis, P1Pk, and Globoside. Protein blood group systems may be single-pass proteins (e.g., MNS and Kell), multipass proteins (e.g., Rh, Duffy, Kidd, and Diego), and glycosylphosphatidylinositol (GPI)-linked proteins (e.g., Cromer, Cartwright, and Dombrock), integral proteins (e.g., Lutheran), or water channel proteins/aquaporins (e.g., Colton and GIL). At the heart of immunohematology is detecting these antigens on red blood cells (RBCs) and the corresponding antibodies individuals may produce. As a general rule, those who lack carbohydrate antigens may produce "naturally" occurring or nonred cell stimulated IgM antibodies without exposure to foreign RBC antigens. In contrast, those individuals who lack protein antigens may produce IgG alloantibodies when exposed to foreign RBC antigens, typically via transfusion or pregnancy. Of course, the immune system "does not read the books" and there are examples of IgG antibodies to carbohydrate antigens and IgM antibodies to protein antigens, albeit unusual. This chapter provides an overview of blood groups, their unique characteristics, and the problems that arise during testing.