Hepatic fibrosis is the common wound-healing response to chronic liver injury. In this process, activation of hepatic stellate cells is characteristic of cell proliferation and migration, production of collagen and other extracellular matrix (ECM) molecules, and contraction after transforming into myofibroblasts. It has been shown that the fibrogenic process is prominently regulated by transforming growth factor-beta1 (TGF-beta1) and that the specific blockade of TGF-beta1/Smad3 signaling may therapeutically intervene the fibrosis of various tissues. In this review, we attempt to integrate recent advances in the understanding of the mechanisms underlying TGF-beta1/Smad3 pathway modulation of ECM gene expression in the context of liver fibrosis, discuss intervention strategies targeting the blockade of related signal pathways, and look into novel ways to the safe and efficacious prevention and treatment of hepatic fibrosis.