Human blood groups are critical for transfusion medicine, organ transplantation, and understanding susceptibility to infectious and autoimmune diseases. The ABO and Rhesus (Rh) systems are the most clinically relevant, defined by surface antigens on erythrocytes. Here, we review the genetic mechanisms governing blood group expression and their physiological and clinical consequences. The ABO locus on chromosome 9 encodes glycosyltransferases responsible for the A and B antigens, with co-dominant inheritance patterns, while the O allele produces a nonfunctional enzyme. The Rh system, primarily determined by the RHD gene on chromosome 1, dictates Rh positivity and negativity, with implications for the hemolytic disease of the newborn. We discuss antigen–antibody interactions, natural and alloimmune responses, and the molecular basis of rare blood group systems such as Kell, Duffy, and Kidd. Integration of genomic, biochemical, and population studies provides insight into the evolution of blood group diversity, their functional roles in pathogen resistance, and the molecular basis of transfusion reactions. Understanding the genetics and physiology of blood groups not only informs clinical practice but also enhances the knowledge of human evolution and disease susceptibility.