Liver fibrosis, a wound-healing response to a variety of chronic stimuli, is characterized by excessive deposition of extracellular matrix (ECM) proteins, of which type I collagen predominates. This alters the structure of the liver leading to organ dysfunction. The activated hepatic stellate cell (HSC) is primarily responsible for excess collagen deposition during liver fibrosis. Two important aspects are involved in mediating the fibrogenic response: first the HSC becomes directly fibrogenic by synthesizing ECM proteins; second, the activated HSC proliferates, effectively amplifying the fibrogenic response. Although the precise mechanisms responsible for HSC activation remain elusive, substantial insight is being gained into the molecular mechanisms responsible for ECM production and cell proliferation in the HSC. The activated HSC becomes responsive to both proliferative (platelet-derived growth factor) and fibrogenic (transforming growth factor-beta[TGF-beta]) cytokines. It is becoming clear that these cytokines activate both mitogen-activated protein kinase (MAPK) signaling, involving p38, and focal adhesion kinase-phosphatidylinositol 3-kinase-Akt-p70 S6 kinase (FAK-PI3K-Akt-p70(S6K)) signaling cascades. Together, these regulate the proliferative response, activating cell cycle progression as well as collagen gene expression. In addition, signaling by both TGF-beta, mediated by Smad proteins, and p38 MAPK influence collagen gene expression. Smad and p38 MAPK signaling have been found to independently and additively regulate alpha1(I) collagen gene expression by transcriptional activation while p38 MAPK, but not Smad signaling, increases alpha1(I) collagen mRNA stability, leading to increased synthesis and deposition of type I collagen. It is anticipated that by understanding the molecular mechanisms responsible for HSC proliferation and excess ECM production new therapeutic targets will be identified for the treatment of liver fibrosis.