The pathogenesis of autoimmune disease is still an enigma. Whereas the diverse clinical manifestations of many autoimmune diseases cannot be explained by the existence of autoantibodies, idiotypic dysregulation may provide an alternative explanation. Experimental models, serum level changes of pathogenic idiotypes during exacerbation and remission, and the increased expression of pathogenic idiotypes following common infections all support this notion. In this article we review experimental models of autoimmune disease induction (systemic lupus erythematosus, antiphospholipid syndrome, Goodpasture's syndrome, autoimmune thyroiditis, and vasculitis) by manipulation of the idiotypic network, and discuss the utilization of idiotypes for the immunotherapy of autoimmune diseases and other conditions that involve the immune system (e.g., atherosclerosis).