Autoimmune diseases are threatening an increasing number of patients in developed countries, representing one of the major causes of disability and an enormous social cost. Current therapies mainly treat the symptoms of autoimmune diseases and are only partially able to interfere with disease evolution, and therefore decrease the degree of physical impairment. Thus, the development of new therapeutic strategies is imperative. This review focuses on gene therapy, as one possible alternative approach to the treatment of autoimmune disorders. The potential of gene therapy to specifically target tissues affected by autoimmune aggression, and its ability to interfere with the destructive pathogenic process while providing functional replacement and fostering reparative mechanisms will be emphasized. Gene therapy studies in experimental models of diabetes, rheumatoid arthritis and multiple sclerosis are reviewed.