This chapter discusses physiological basis of transfusion medicine, where the best way to replace any significant blood loss is a blood transfusion. Blood groups are based on the type of antigens present on the surface of red blood cells (RBC). Reaction between a blood group antigen and its corresponding antibody leads to clumping of RBC. Blood groups are genetically determined. ABO system of blood grouping is based on the presence or absence of two antigens, A and B, on the surface of RBC. Mismatch transfusion reactions may occur even if blood groups of donor and recipient are identical. The homozygous or heterozygous state determines the type of contributions the individual can make to the progeny. Platelet concentrates should be given only when absolutely necessary because of their highly immunogenic nature. Blood group antigens are also known as agglutinogens and the corresponding antibodies are called agglutinins.