The rational treatment of systemic sclerosis can be based on a model of its pathogenesis. This model posits a genetic background upon which external stimulae act, resulting in immune activation, vascular injury, fibroblast proliferation, and collagen deposition. The collagen, in turn, increases immune activation, thus resulting in perpetuation of the activation/injury cycle. If this pathogenetic model holds true, intervention can occur at the level of vascular damage, prevention of fibrosis or immunosuppression. Prevention of vascular damage and improvement of oxygenation has been attempted with prostacyclin derivatives, with mixed results. Prevention of fibrosis with interferon-gamma shows some hopeful results in pulmonary fibrosis. Relaxin, too, seems to hold hope for efficacy, whereas the results of therapy with D-penicillamine have been disappointing. Immunosuppression with chlorambucil has not been effective, but the study design was flawed in that trial. Methotrexate may work, but results are mixed. 5-Fluorouracil seems effective, but may be toxic. Cyclophosphamide is effective in open trials, and well-controlled trials are just starting. Finally, stem cell transplantation, a very aggressive form of immunosuppression, is showing some apparent efficacy, but its use is only in the pilot stages.