Systemic sclerosis (SSc) is characterized by extensive fibrosis, vasculopathy and activation of the immune system. Fibrosis can be caused by profibrotic cytokines, such as transforming growth factor-beta (TGFbeta), interleukin-4 (IL-4), platelet-derived growth factor (PDGF), and connective tissue growth factor. Vasculopathy can be caused by TGFbeta, PDGF, while paucity of vessels in skin lesions can be attributed to anti-endothelial cell autoantibodies. Recent studies have suggested that the activation of the immune system is of paramount importance in the pathogenesis of SSc. T Cells are activated by antigen, infiltrate early the skin lesions in SSc, and produce the profibrotic cytokine IL-4. They are also required for autoantibody production. B cells may contribute to fibrosis, as deficiency of CD19, a B cell transduction molecule, results in decreased fibrosis in animal models of fibrosis. These new developments have direct impact on the treatment of SSc. Medications directed against immune cells or harmful soluble factors in small trials in SSc are encouraging.