Autoantibodies against double stranded (ds) DNA are not only a helpful serological marker for diagnosis of systemic lupus erythematosus (SLE), but have also been shown to be crucial in the pathogenesis of lupus nephritis. However, the question of how anti-dsDNA antibodies contribute to renal damage is unresolved. Many authorities believe that indirect binding (mediated by nuclear antigens) or direct cross-reactivity of anti-dsDNA antibodies with kidney antigens are important determinants of anti-dsDNA nephritogenicity. An alternative hypothesis for the renal pathogenicity of anti-dsDNA antibodies was proposed more than 20 years ago, namely that certain autoantibodies could penetrate into living cells and thus induce damage. Work from several laboratories has recently provided firm support for this iconoclastic theory, which contradicted prevailing immunologic dogma that cell interiors are inaccessible to antibodies. Here, we review the evidence that anti-dsDNA antibodies may penetrate into living cells, and discuss which intracellular events may follow from binding of anti-dsDNA antibodies to the cell surface and subsequent intracellular penetration. Determining the mechanism by which anti-dsDNA antibodies induce renal injury is important for understanding a major disease manifestation of lupus, and may lead to the development of novel approaches to the treatment of lupus renal disease.