Systemic lupus erythematosus (SLE) is a multisystemic disease characterized by alterations in the regulation of both cellular and humoral immune responses. B cell hyperactivity and genetic aberrations lead to formation of compliment-fixing IgG autoantibodies including anti-DNA and anti-nucleosome antibodies. Pathological T cell clones that recognize double-stranded DNA and nucleosomes further drive B cell production of DNA autoantibodies. Deposition of autoantibodies within the skin, kidney, brain, and other organ systems contributes to the pathophysiology and clinical manifestations of SLE. A growing body of experimental evidence indicates that DNA antibodies contribute to the histological changes observed in lupus nephritis. The binding of anti-DNA and other autoantibodies to basement membranes and other cellular structures within the glomerulus results in activation of compliment and recruitment of inflammatory cells into the glomerulus. The use of high-dose steroid hormones and cytotoxic agents have improved patient and renal survival, but are associated with major infection, infertility, osteoporosis, and secondary malignancies. New pharmacological approaches to the treatment of lupus nephritis will include drugs that deplete specific B cell clones involved in the synthesis of nephritogenic autoantibodies as well as the blocking of signal transduction pathways required for antigen-dependent antibody synthesis. Novel clonal-specific approaches to immunosuppression in patients with SLE offer the potential for precise targeting of the disease pathogenesis and for reducing toxic complications of treatment.