Systemic lupus erythematosus (SLE) is the archetypic non-organ specific autoimmune disease in which polyclonal B-cell activation is reflected by the wide range of auto-antibody specificities. Among these, anti-ds DNA antibodies bear special significance since they are disease specific, tend to occur at high titers in an active clinical state and are considered to be pathogenic through immune complex formation. However, data accumulated in the last few years have led to a somewhat more complex view of anti-DNA autoantibodies and SLE pathogenesis. For instance, the definition of pathogenic subpopulations of anti-DNA antibodies is an important question which has been addressed in terms of isotypes, idiotypes and DNA sequences of antibodies. Also, some of the cross reactivities described with monoclonal anti-DNA antibodies appear to be due to the formation of immune complexes with DNA, histones or nucleosomes. In addition, anti-DNA-nucleosome immune complexes can react with the cell membrane. These findings indicate that not only DNA but also the nucleosome as a multimolecular complex or its non-DNA component, i.e. histone, may be viewed as relevant target autoantigens in SLE. This review will focus on experimental data supporting this new representation of this set of autoantibodies directed against DNA, histone and the nucleosome, and their possible intervention in SLE pathogenesis.