The ABO blood group system, which was described by Karl Landsteiner in 1901, has transformed transfusion medicine by improving the science of blood compatibility. Blood A, B, AB, and O are the four principal blood group systems present based on the presence or absence of the A and B antigens in red blood cells (RBC). This system is important in immunology, genetics, and evolutionary biology and also, its scope is not limited to blood transfusion safety but to how it also affects infections and treatment. ABO antigens are formed by glycosyltransferases that are under the control of the ABO gene which allows the modification of the H antigen, forming A and B antigens. Individuals with blood group O are genetically incapable of producing these enzymes hence the H antigen remains unchanged. More complexities are introduced in the system by the allelic polymorphisms of the ABO and H antigen genes with respect to their occurrence and known variations such as the Bombay blood group. It is important to appreciate the molecular, genetic, and immunological aspects of the ABO system and to apply this knowledge in clinical transfusions, organ transplantation, and hemolytic disease prophylaxis.