Immediate, short- and long-term adverse events of classical immunosuppressor drugs strongly stimulate novel, but less toxic approaches. Combined or sequential use of cyclophosphamide, mycophenolate mofetil and/ or azathioprine should improve clinical tolerance and avoid severe adverse events (infections, infertility, amenorrhea), regularly associated to long term therapies with classical immunosuppressive schemes. Among novel developments based on biologicals, the anti-CD20 monoclonal antibody rituximab (anti-B cells) appears encouraging in open studies, in association or not with cyclophosphamide, and is generally well tolerated. Further information is expected from the inhibitor of T cell/B cell co-stimulation CTLA4-Ig, or from strategies aiming to inhibit key cytokines in SLE pathogenesis such as interferon-alpha, IL-1 or IL-6.