The ultimate goal in the treatment of autoimmune diseases is to restore immune tolerance to the relevant target antigen(s). Short of this ideal, the attenuation of pathogenic immune responses is a highly desirable end. Many forms of immunotherapy are being studied with these objectives in mind, but gene transfer approaches, and particularly DNA vaccination (transfer of an antigen gene), are promising. DNA vaccination is most often performed by nonviral techniques, such as the intramuscular (i.m.) injection of naked plasmid DNA. In addition to antigen delivery, this approach permits local or systemic delivery of immunomodulatory molecules (DNA covaccination). As reviewed below, DNA vaccination strategies have been employed to ameliorate autoimmune insulin-dependent diabetes mellitus (type 1 diabetes [TID]), experimental autoimmune encephalomyelitis (EAE) and other au-toimmune diseases.