Multiple etiologies of liver injury can lead to fibrosis, which results from an imbalance between production and resorption of extracellular matrix. Hepatic stellate cells (HSCs), resident vitamin A storing cells, play a vital role in the response to injury. Upon activation, HSCs orchestrate the responsiveness of the liver to different types of injury, leading to deposition of excessive scar matrix into the interstitium as a wound-healing response. Quantitatively and qualitatively, the altered extracellular matrix (ECM) provides a permissive milieu for the development of cellular dysplasia and ultimately hepatocellular carcinoma (HCC). There is a range of underlying mechanisms that contribute to progression of fibrosis to HCC. As the functional complexity of HSC activation and its roles in inflammation, immune responses, angiogenesis, and proliferation are being clarified, new advances in therapeutic options for patients with chronic liver disease are emerging.