Despite some confusion in the literature, drug-induced SLE is a well defined reversible clinical entity. The lupus syndromes induced by procainamide, hydralazine, and isoniazid have been well studied and the data obtained have been convincing. Other drugs may also induce a lupus syndrome, but adequate prospective studies have not been done. Furthermore, many other drugs previously incriminated appear to activate spontaneous SLE rather than induce the de novo lupus syndrome. The mechanism by which procainamide, hydralazine, and isoniazid exert their effect is not known, and animal studies have been unrewarding. However, hydralazine and procainamide are capable of complexing with nuclear antigens in vitro and possibly in vivo and may evoke antinuclear antibody responses in this way. A number of defined factors influence the development of the clinical syndrome, including the cumulative drug dosage, the acetylator phenotype of the individual, and the biochemical nature of the drug. Studies to date have not revealed how these drugs induce the clinical disease. While these agents may induce antinuclear antibodies in many individuals, genetic influences may be important in determining which patients will develop clinical symptoms. Further study of drug-induced systemic lupus erythematosus is necessary in order to resolve these problems regarding pathogenesis. The resolution of these problems may shed light on the pathogenesis of spontaneous SLE.