The a priori biologic significance of the histocompatibility complex with its excessive polymorphism remains unknown. Teleologically, however, the role of the HLA system may be viewed as vital for survival of the species and the individual by providing the host with a recognition system of and defenses against viruses, microorganisms, parasites, plant antigens, neoplastic cells, and others. HLA testing, in addition to its usefulness in donor selection for transplantation, has been recently applied to the diagnosis and differentiation of specific diseases, the prediction of disease development (risk prediction), and as a basis for prognostic evaluations. An increasing number of diseases is being shown to be linked by specific HLA antigens and certain common denominators, such as arthritides, autoimmune components or infections, suggesting common etiologic or pathogenic mechanisms or both. These diseases with HLA associations can be separated into those that appear certain, probable, or only statistically possible.