Connective tissue growth factor (CTGF) is over expressed in lung fibroblasts isolated from patients with interstitial lung disease (ILD) and systemic sclerosis (SSc, scleroderma) and is considered to be a molecular marker of fibrosis. To understand the significance of elevated CTGF we investigated the changes in lung fibroblast proteome in response to CTGF overexpression. Using two-dimensional gel electrophoresis (2-DE) followed by mass spectrometric analysis, we identified 13 proteins affected by CTGF. Several of the CTGF-induced proteins, such as pro- (I) collagen and cytoskeletal proteins vinculin, moesin and ezrin, are known to be elevated in pulmonary fibrosis, whereas nine of 13 proteins have not been studied in pulmonary fibrosis and are, therefore, novel CTGF-responsive molecules which may have important roles in ILD. Our study demonstrates that one of the novel CTGF-induced proteins, IQ motif containing GTPase activating protein (IQGAP)1, is elevated in lung fibroblasts isolated from scleroderma patients with ILD. IQGAP1 is a scaffold protein that plays a pivotal role in regulating migration of endothelial and epithelial cells. Lung fibroblasts treated with CTGF demonstrated increased rate of migration in a wound healing assay. Depletion of IQGAP1 expression by small interfering (si)RNA inhibited CTGF-induced migration and Erk1/2 phosphorylation in lung fibroblasts. MAPK inhibitor decreased CTGF-induced cell migration and did not interfere with IQGAP1 expression suggesting that MAPK pathway is downstream of IQGAP1. These findings implicate the importance of CTGF in lung tissue repair and fibrosis and propose that CTGF-induced migration of lung fibroblasts is mediated via IQGAP1 and MAPK signaling pathways.