Among the autoantibodies that are known to play a role in the pathogenesis of autoimmune diseases, antibodies to DNA (anti-DNA) have been the subject of much study. Several interesting observations have resulted. The ability to make antibodies that bind DNA is not abnormal. Normal mice and humans can produce antibodies that bind DNA. On the other hand, large quantities of antibodies to DNA are found in the sera of patients with systemic lupus erythematosus (SLE), and complement-fixing antibodies to double-stranded (ds) DNA cause some of the tissue lesions, especially glomerulonephritis (GN). Why, then, do some individuals make anti-DNA that deposits in glomeruli, skin, and other tissue, resulting in organ damage? It is likely that disease results from a combination of several factors--ability to make pathogenic antibody subsets, inability to downregulate those subsets, and "tissue susceptibility" to injury from those antibodies and their immune complexes. This chapter will focus on the characteristics of pathogenic antibody subsets and their regulation.