This article emphasizes the interpretation of the meaning and significance of the genetic aspects of susceptibility to certain autoimmune-mediated rheumatic diseases. The familial aggregation and identical twin concordance that provides the basis of considering these as genetic diseases are reviewed. Major histocompatibility complex (MHC) genes are taken as the primary examples of candidate genes that regulate the immune response; the potential function of these genes in predisposing to autoimmune diseases is analyzed. Autoimmune diseases are discussed as the consequence of the role of MHC molecules encoded by different alleles that exhibit distinct peptide-binding properties and select a self reactive T-cell repertoire. The low penetrance rates of autoimmune-mediated rheumatic disease is used as an argument that stochastic events in the generation and postthymic maturation of the somatically expressed T-cell repertoire account for the characteristically delayed onset of these diseases. The importance of self-reactivity in the physiologic immune response is used as an argument that the events that are responsible for the development of an autoimmune disease are an untoward exaggeration of normal immune responsiveness, but not a qualitatively distinct biologic event.