Excessive connective tissue deposition in the skin and other organs is the pathologic hallmark of systemic sclerosis (SSc), and fibrosis accounts for much of the chronic morbidity of this disease. Unregulated production of collagen in SSc skin fibroblasts has been demonstrated both in vivo and in vitro, and is considered to be a critical process in the development of fibrosis. In addition to collagen, other components of the extracellular matrix are also overexpressed in SSc fibroblasts, and may be important in the functional alterations of connective tissue. The transcriptional activity of several genes coding for matrix macromolecules is upregulated in SSc fibroblasts. The pleiotropic signaling molecule transforming growth factor-β (TGFβ) is likely to be intimately involved in initiating and perhaps perpetuating the fibrotic response in SSc. TGFβ, a potent profibrotic cytokine, is highly expressed in endothelial cells, in fibroblasts near blood vessels, and in perivascular inflammatory cells in involved tissues in SSc. The apparent failure of SSc fibroblasts to down-regulate their collagen synthesis when cultured in a three-dimensional matrix suggest an additional mechanism for the maintenance of unregulated collagen production in these cells. Finally, subpopulations of fibroblasts with an activated biosynthetic phenotype may become dominant in SSc. Therefore, persistent elevation of extracellular matrix gene expression in SSc tissues may be the result of a series of events representing the interaction of genetic and hormonal factors. A precise delineation of the mechanisms of fibroblast activation is needed for understanding the pathogenesis of SSc, and for the rational design of therapeutic interventions aimed at interfering with the fibrotic process.