Nucleic acid binding autoantibodies are the hallmark of the human autoimmune disease, systemic lupus erythematosus (SLE) and are also prevalent in mouse models of this disease. The immunologic stimuli for the production of these antibodies as well as their pathogenic mechanisms are not well understood. However, extensive immunochemical and genetic studies, together with initial crystallographic analysis and computer modeling, have suggested several structure-function correlates which will form the basis for future research. The anti-DNA and anti-RNA autoantibodies comprise a continuous spectrum of specificities in which a delicate balance exists between the binding to the sugar-phosphate backbone and the interactions with the heterocyclic bases of the nucleic acid. Prominent in these interactions are the products of specific V-region immunoglobulin genes, some of which appear to be uniquely suitable for nucleic acid binding. Other structural elements encoded by D minigenes, N sequences and somatic mutations, help to increase the affinity of the binding interaction, and may also increase the repertoire of nucleic acid binding antibodies by combining with a relatively large number of additional V-gene products. Initial crystallographic analyses of anti-DNA antibodies indicate some fundamental differences in the structure and shape of ssDNA and dsDNA antibody combining sites. However, they also suggest a considerable degree of flexibility of both antibody and antigen, which is induced by their binding interaction.