Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by a chronic inflammation affecting multiple tissues and the production of antibodies directed against nuclear antigens. Leading observations in patients suggested years ago that interferon-alpha (IFNalpha) was involved in SLE pathogenesis. These observations have now been confirmed in SLE-prone mice. New promising therapeutic strategies, aiming at neutralizing IFNalpha or its effects, are currently under development.