Publisher Summary This chapter discusses the recent developments made in the production and assay of antibodies to nucleic acids, structural analyses of specific antibody/nucleic acid interactions, and the applications of the antibodies as biochemical reagents. There has been much progress in the structural analysis of the way antibodies recognize a variety of nucleic acid epitopes in single bases, nucleosides and nucleotides, short oligonucleotides, single stranded DNA, RNA, certain double- and triple-helical polynucleotides, and variants such as cruciform structures. The definition of specificity (and, in some cases, of cross-reactivity) for nucleic acid epitopes has been greatly facilitated by the preparation of hybridomas that produce monoclonal antibodies. In recent years, hybridomas have also allowed the analysis of the genes that encode the variable regions of antibodies to nucleic acids. The heavy- and light-chain variable-region cDNAs of many auto-antibodies to DNA and a few experimentally induced antibodies have been cloned and sequenced. Very diverse amino-acid sequences make up the complementarity determining regions loops of the many antibodies for which the primary structure is known. This information, along with the development of plasmid vectors that allow the expression of immunoglobulin genes and production of recombinant antibody fragments, opens the door to a future in which a rich variety of specific nucleic-acid-binding reagents may be designed and synthesized. In the course of such research, much has been learned about the many ways in which proteins can interact specifically with nucleic acids.