In 1997, the discovery of autoantibodies reactive with DNA celebrates its fortieth anniversary. Over these 4 decades, hardly any other single spontaneously produced antibody population has been subjected to such a wide scientific interest both from a basic immunological as well as from a clinical point of view. From the time of their first description, myths and enigmas regarding their biological origin have dominated the scene. Only during the last few years results have been obtained that have justified new conceptual frameworks for the understanding of the molecular bases for their production, as well as for their pathophysiological potential in systemic lupus erythematosus (SLE). Central, newly obtained experimental and clinical results that have profoundly improved our understanding of the origin and biology of anti-DNA antibodies will be presented and discussed below.