Systemic sclerosis is a multisystem disease whose therapy is focused at pathogenic pathways causing variable types of damage in the individual organs. There are 3 major pathways that cause organ damage in scleroderma. First, t-cells, cytokines and inflammation are prominent very early in the disease. Early alveolitis which occurs before interestial fibrosis in the lungs is the best example of inflammation. Second, endothelial cell damage causes severe thickening of vessels and two of the most deadly complications in scleroderma, pulmonary arterial hypertension and renal crisis. Scleroderma renal crisis is now very treatable with angiotensin converting enzyme inhibitors. There are now treatments for pulmonary arterial hypertension which should improve outcome in these patients as well. Third, fibroblasts lead to severe cutaneous fibrosis or skin thickening that is the hallmark of the disease. No treatment is available but we are hopeful that new antagonists to the cytokine, TGF beta, will prove helpful. B cells and autoantibodies are not involved in the pathogenesis of the disease, but there are scleroderma specific antibodies that help in defining patient subsets. All of these factors are influenced by unknown inciting agents and the permissive genetic background.