Systemic sclerosis (SSc) is a complex fibrosing autoimmune disease that has variable clinical manifestations and morbidity/mortality secondary to organ damage due to vasculopathy and/or fibrosis. Initial events in the pathogenesis are manifested by fibroproliferative vasculopathy that compromises delivery of blood to critical organs. There is evidence of autoimmunity early in the disease which persists and is accompanied by fibrotic processes that leave large accumulations of collagen and other matrix components in the intima of blood vessels and extracellularly in the connective tissue of organs affected by the disease. It has recently been realized that the lysophospholipids -- lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), which are elevated in sera of SSc patients, are capable of producing many of the abnormalities observed in the vasculature, immune system, and connective tissue of patients with this disease. This article reviews key abnormalities of the vasculature, immune system, and connective tissue in SSc that could be mediated by LPA/S1P.