The Rh blood group system is one of the most polymorphic and immunogenic systems known in humans. In the past decade, intense investigation has yielded considerable knowledge of the molecular background of this system. The genes encoding 2 distinct Rh proteins that carry C or c together with either E or e antigens, and the D antigen, have been cloned, and the molecular bases of many of the antigens and of the phenotypes have been determined. A related protein, the Rh glycoprotein is essential for assembly of the Rh protein complex in the erythrocyte membrane and for expression of Rh antigens. The purpose of this review is to provide an overview of several aspects of the Rh blood group system, including the confusing terminology, progress in molecular understanding, and how this developing knowledge can be used in the clinical setting. Extensive documentation is provided to enable the interested reader to obtain further information. The Rh blood group system is the most polymorphic of the human blood groups, consisting of at least 45 independent antigens and, next to ABO, is the most clinically significant in transfusion medicine. The ability to clone complementary DNA (cDNA) and sequence genes encoding the Rh proteins has led to an understanding of the molecular bases associated with some of the Rh antigens. Serologic detection of polymorphic blood group antigens and of phenotypes provides a valuable source of appropriate blood samples for study at the molecular level. This review summarizes our present understanding of the complexities of Rh blood group expression and how this knowledge impacts on clinical situations that arise through Rh blood group incompatibility.