Antibodies to DNA occur prominently in systemic lupus erythematosus and have been extensively studied as probes for underlying immune disturbances. These antibodies have features of DNA antigen drive. While previous models for this response posited DNA as simple and inert, recent studies have indicated that DNA is immunologically diverse and, depending upon sequence and backbone structure, can stimulate or suppress immune responses. In particular, bacterial DNA is immunologically potent and can function as both an adjuvant and immunogen, eliciting in normal individuals antibodies to sites exclusive to bacterial DNA. In mice genetically predisposed to autoimmunity, however, bacterial DNA can elicit anti-DNA autoantibodies under conditions in which mammalian DNA is inactive. These findings suggest that foreign DNA can serve as a trigger for anti-DNA responses, with SLE reflecting a disturbance in antibody specificity and a shift from binding of sequential to backbone determinants. In contrast to bacterial DNA, mammalian DNA can suppress certain immune responses and prevent macrophage cytokine production. To the extent that self-DNA drives responses in SLE, anti-DNA production in this disease may reflect a failure of this suppression. The recognition of DNA's immune activities thus suggests novel possibilities for disease pathogenesis.