Complex pathogenic processes lead to heterogeneous manifestations in autoimmune diseases. Except for rare patients in whom a single genetic defect—in genes for the Fas ligand or for the complement factors C4, C2, or C1q—is associated with autoimmune manifestations, these diseases are multifactorial. Complex genetic, environmental, and immunoregulatory factors appear to play out in a process that we understand in only a fragmentary sense and that we have little ability to influence (1). Therefore, gene therapy involving the reconstitution of a single missing gene should be expected to be of minimal help in treating these diseases. Our current practice of helping patients symptomatically, or at best by indiscriminate suppression of the immune system, is obviously inadequate. Correction of the identified immunoregulatory aberrations has become the mainstay of the efforts to treat autoimmune disorders in a rational manner. Therapeutic intervention in autoimmune disease faces formidable challenges, since it requires a balance between the control of ongoing pathogenic immune responses and the maintenance of essential immune surveillance functions. Therapies directed at general pathways of immune activation or amplification are antigen-nonspecific and may allow for widespread application across multiple diseases, but they also carry the risk of global immunosuppression. Antigen-specific therapeutics, on the other hand, are potentially much more selective and less deleterious, but they require a priori knowledge of precise immunologic targets relevant in each autoimmune setting. Cytokines, cytokine antagonists, anti–T cell monoclonal antibodies, inhibitors of signal transduction, and conventional pharmacologic agents fall into the former group, whereas specific peptide antigens, antagonists, and MHC-antigen complexes fall into the latter group of treatments. Table 1 summarizes many of the approaches that have been tested in mouse models of various autoimmune disorders. In this issue of the JCI, articles by Agarwal et al.(2) and Lawson et al.(3) apply novel forms of gene therapy to introduce directed immune therapeutics in autoimmune animals, illustrating both antigen-nonspecific and antigen-specific strategies.