Part of the difficulty in finding effective treatments for SSc has been a continuing uncertainty regarding what initiates pathogenesis. The cause of disease manifestations in SSc remains obscure, although three major pathophysiologic explanations have been advanced. Prominent pathologic changes in dermal and pulmonary tissues show fibrosis, suggesting abnormalities in matrix deposition. Vascular disease, resulting in scleroderma renal crisis, digital ischemia and pulmonary hypertension suggests dysfunction of the vascular endothelium. Autoantibodies in SSc patient sera suggest that immune dysfunction and autoimmunity may contribute to or cause disease. The different pathological features in different organs have provided support for each of these mechanisms, but not clarified which is most important in overall pathogenesis.