Histocompatibility antigens, virus infections, and disease are discussed relative to avenues of research in humans with arenavirus infections. The data implicating a relationship between histocompatibility complexes in man and animals and diseases of the central nervous system are reviewed. Histocompatibility antigens may share common antigenic determinants with viruses, act as receptor sites for attachment of viruses, and be altered by viruses. In addition, genes regulating immune responses to a variety of natural and synthetic antigens are linked, in many species, to the major histocompatibility complex. Since injury associated with virus infections may be largely due to the activity of the immune system, study of immune response genes may provide insight into understanding resistance to disease. Further, histoincompatibility reactions can activate latent viruses with resultant disease.