The primary structure of anti-DNA antibodies is highly diverse, a result of different germline variable (V) gene use, different combinations of immunoglobulin gene segments, peculiar heavy chain complementarity determining region 3 (H-CDR3) segments, and somatic mutations. Nevertheless, tertiary structure predictions reveal common features that yield information about likely contact sites in the anti-DNA combining site. That these contacts are involved with DNA binding is supported by recurrent features of a newly compiled set of homology groups of 13 variable regions of heavy chains (VH) and 11 variable regions of light chains (VL), characteristic pattern of somatic mutations, and the results of site-directed mutagenesis. The role of antigen in the etiology of the autoimmune response is viewed in light of recent data on overlaps between anti-DNA and anti-nucleic acid binding protein specificities.