At present, the mechanisms that regulate the expression of collagen genes in normal and pathologic fibroblasts are not known. Thus, the detailed study of transcriptional regulation of COL1A1 in SSc cells will increase our current understanding of the pathophysiology of fibrotic diseases. These studies will yield valuable information regarding the important biological process of regulation of collagen gene expression under normal and pathologic conditions, a process that has remained elusive despite intense recent investigations. It is now evident that persistent overproduction of collagen is responsible for the progressive nature of tissue fibrosis in SSc. Up-regulation of collagen gene expression in SSc fibroblasts appears to be a critical event in this process. The coordinate transcriptional activation of numerous collagen genes suggests a fundamental alteration in the regulatory control of gene expression in SSc fibroblasts. Trans-acting nuclear factors which bind to cis-acting elements in enhancer (intronic) and promoter regions of the genes modulate the basal and inducible transcriptional activity of the collagen genes. The identification of the nuclear transcription factors that regulate normal collagen gene expression may provide promising approaches to the therapy of this incurable disease.