Gene therapy is currently being explored as a new therapeutic treatment of autoimmune disease. The genetic modification of autoreactive memory T cells (T cell-mediated gene therapy) and autoimmune target tissue (target tissue gene therapy) to produce immunoregulatory cytokines offers a promising way to regulate autoimmunity. Furthermore, regenerative gene therapy offers the possibility of delivering growth factors to damaged autoimmune target tissue as a way of mediating repair. In the current review we discuss the different experimental models that are being used to test the efficacy of gene therapy in that treatment of autoimmune disease. We also discuss the importance of regulating transgene expression to ensure the therapeutic transgene products are delivered specifically to the autoimmune milieu in an antigen-inducible, non-constitutive manner.