In numerous animal models, DNA immunization has been shown to induce protective immunity against infectious diseases (viral, bacterial and protozoan) and cancers (1, 2). In these situations it is desirable to induce a strong immune response to the DNA-encoded antigen in order to generate an immune memory that enables the vaccine to respond more rapidly to subsequent challenge. The success of DNA vaccination in this regard has led to its rapid introduction into several human clinical trials (3, 4). However, in autoimmunity, undesirable immune responses to autoantigens are thought to lead to the destruction of target cells or organs, resulting in diseases such as myasthenia gravis, diabetes or multiple sclerosis. Thus, at first sight, it appears that immunization would more likely trigger autoimmunity than ameliorate it. Nevertheless, clinical experience has shown that certain immune-mediated diseases may be countered by low-dose antigen administration ('desensitization'), although the underlying mechanisms remain somewhat conjectural. Here, we will describe an intriguing approach to the prevention of autoimmune disease, in which we use a DNA vaccine encoding a self-antigen to abrogate autoimmune diabetes. The success of this strategy relies on the nature of the immune response induced by the DNA vaccine.