Gene therapy as a concept usually seeks to replace a defective or missing protein in order to restore a desired function. The concept typically implies that diseases amenable to this approach are of monogenic origin; indeed, monogenic disorders have received the most research attention. Polygenic diseases are conceptually different in terms of formulating a gene therapy strategy, and include autoimmune diseases in the category. For the treatment of autoimmune diseases by gene therapy approaches, the rationale is not to replace missing or malfunctioning proteins, but to deliver proteins, by either ex vivo or in vivo gene transfer, in an attempt to modify the response of the immune system. In addition, the strategy for the induction of immune tolerance can be either a broad approach, in which large parts of the immune response are reset, or can be tailored to be more specific, focusing on autoantigen-directed effector cells. Gene therapy protocols for autoimmune disease are still largely experimental. For each type of autoimmune disease, the risk-to-benefit ratio varies, depending in part on the severity of disease. It is unclear when gene therapy approaches will be evaluated in clinical trials; however, as progress in safety and advances in understanding true antigen-specific tolerance occur, gene therapy is likely to become available for clinical use.