Anti-DNA antibodies are the serologic hallmark of systemic lupus erythematosus and important markers for diagnosis and prognosis. Although a number of mechanisms for anti-DNA production have been proposed, recent evidence from human as well as murine lupus indicate a prominent role of DNA antigen drive. To identify further the basis of this response, current research is focusing on the structural features of DNA associated with immunogenicity in both the normal and autoimmune settings. Elucidating these mechanisms should thus provide insights into the pathogenesis of systemic lupus erythematosus as well as the immunologic activity of nucleic acids.