Antinuclear antibodies occur prominently in systemic lupus erythematosus and serve as markers of underlying pathogenetic disturbances. Although these antibodies display features indicative of genetic control and in vivo selection by self-antigen, other mechanisms shaping the B-cell repertoire may influence their production. Provocative new animal models provide systems for analyzing the cellular and genetic disturbances promoting these responses, as well as the role of pathogenic specificities in inducing tissue injury.