The cause of systemic sclerosis remains unknown, but cellular and molecular mechanisms possibly responsible for the characteristic clinical manifestations of fibrosis and vascular damage (Raynaud's phenomenon, telangiectasias, digital infarction, and renal arteriopathy) are becoming understood in greater detail. One possibly important cytokine is transforming growth factor-β (TGF-β); its involvement is reviewed here. With regard to vascular lesions, TGF-β has variably been shown to inhibit endothelial cell growth in vitro but to promote angiogenesis in vivo, a paradox that remains unresolved. Nonetheless, an injurious activity of TGF-β on microvascular endothelial cells could help to explain the intimal proliferation and microvascular obliteration seen. Whether as a result of or as a cause of endothelial cell damage, platelet activation has been well documented in systemic sclerosis and the platelet a granule pool contains a large quantity of TGF-β. TGF-β is also produced by activated macrophages and T cells, both of which are known to occur within systemic sclerosis lesions. An important effect of TGF-β is its stimulation of fibroblast collagen and flbronectin synthesis and their deposition into the extracellular matrix. Stimulation by TGF-β may therefore account for the fibrosis seen in the dermis and in the internal organs. Direct evidence of TGF-β involvement in systemic sclerosis is scanty, and awaits discovery of either an abnormal expression of or response to TGF-β. The biologic effects of TGF-β appear to be regulated at the level of activation from a latent polypeptide precursor form. Descriptions of the importance of this cytokine in pathologic conditions will need to account for this activation and its regulation. Nonetheless, the physiologic effects so far attributed to TGF-β make its involvement in systemic sclerosis an attractive possibility to explain some of the manifestations of this enigmatic disease.