Recent investigations on the mechanisms of ANA production in the rheumatic diseases suggest that these responses frequently emerge in the setting of nonspecific immunoregulatory disturbances. However, the expansion and maturation of these responses to generate pathogenic specificities may require the coexistence of clonal or antigen-specific abnormalities. At the genetic level, ANAs appear to be of diverse origin, including some with representation in the normal B cell repertoire. Since some ANAs are disease-specific, elucidation of the basis of their production should provide insights into the unique pathogenetic features of different rheumatic diseases.