Excessive extracellular matrix (ECM) deposition in the skin, lung, and other organs is a hallmark of systemic sclerosis (SSc). The pathogenesis of SSc is still poorly understood, but increasing evidence suggests that various cytokines such as transforming growth factor (TGF)-β and their signaling pathways are key mediators of tissue fibrosis as a consequence of ECM accumulation in the pathogenesis of fibrosis such as SSc. TGF-β regulates diverse biologic activities including cell growth, cell death or apoptosis, cell differentiation, and ECM synthesis. TGF-β is known to induce the expression of ECM proteins in mesenchymal cells, and to stimulate the production of protease inhibitors that prevent enzymatic breakdown of the ECM. This paper focuses on the possible role of ECM, various cytokines, especially TGF-β signal transduction pathways in the pathogenesis of fibrosis in SSc.