Systemic sclerosis (SSc, scleroderma) is a complex disease manifesting itself by fibrosis of skin and other internal organs. Fibroblasts isolated from SSc lesions and cultured in vitro are characterized by the increased synthesis of collagen and other extracellular matrix (ECM) proteins, consistent with the disease phenotype. Cultured SSc fibroblasts therefore serve as a principal experimental model for studying the molecular and cellular mechanisms involved in collagen overproduction in this disease. This article provides an overview of transcription factors that are deregulated in SSc fibroblasts. The possible origin of SSc fibroblasts is also discussed.