Systemic sclerosis (SSc, scleroderma) is a connective tissue disease of unknown etiology. Perivascular inflammatory infiltrates and endothelial apoptosis with an impaired angiogenesis are observed in early stages of the disease, whereas later stages are characterized by an excessive accumulation of extracellular matrix proteins in the skin and various internal organs. Consistent with the ongoing endothelial cell damage, various markers of endothelial cells such as endothelin-1, sICAM-1, s-VCAM-1 and thrombomodulin are found in high levels in the serum of SSc patients. Surprisingly, the vascular endothelial growth factor (VEGF), a potent angiogenic molecule, is overexpressed in the skin of patients with SSc despite insufficient angiogenesis. Interestingly, patients suffering from diffuse SSc and patients without finger tip ulcers show higher VEGF levels compared to age- and sex-matched controls. These results indicate that a controlled overexpression of VEGF might help to protect against the manifestation of ischemic conditions. On the other hand, data from animal models indicate that a long-term, uncontrolled overexpression of VEGF might have paradox effects on the formation of new vessels leading to capillary changes similar to those observed in SSc. In addition to the impaired angiogenesis, defective vasculogenesis might contribute to the vascular symptoms of SSc.