Identification of autoantibodies directed against nuclear antigens is a very important finding in the assessment of autoimmune rheumatic diseases. In particular, the anti-DNA autoantibodies have assumed a fundamental importance, both speculative and clinical, in the study of the systemic lupus erythemathous. The aim of the present review is to focalize on anti-DNA the mechanisms of both induction and production of anti-DNA autoantibodies, pathophysiologic and diagnostic and clinical aspects. For this purpose, forty years of studies on this topic have been reviewed. Aspects on different conformational shapes of double-stranded DNA have been discussed such as related pathogenetic and diagnostic ones. Finally, the review has dealt with experimental therapies, focusing on both animal models and the most recent clinical trials according to Evidence Based Medicine.