The predictive potential of anti-dsDNA autoantibodies (AAb) lays on their biological activity and their ability to cause the pathological changes typically found in patients with SLE. In this review, we discuss old and recent evidence that supports the idea of AAb against dsDNA may cause directly tissue damage. Tissue deposition, Ab isotype, affinity maturation, and its ability to activate complement and engage Fc receptors are the classical determinants of the pathogenicity of anti-dsDNA AAb. Furthermore, there is strong evidence that suggest that anti-dsDNA AAb of the IgG isotype are able to shuttle nuclei acid fragments through the plasma membrane causing activation and secretion of inflammatory cytokines. Nucleic acid-containing immune complexes may thus serve as a virus-mimeticum.