Liver fibrosis contributes to many of the devastating complications of viral, toxic, fatty, and cholestatic liver disease. Understanding the cell populations that promote liver fibrosis and the molecular pathways through which they operate is essential for the development of antifibrotic therapies. The authors review the origins and functions of hepatic myofibroblasts, focusing on hepatic stellate cells, the main contributors to organ fibrosis, and portal fibroblasts, an insufficiently characterized population that may have a specialized function in promoting periductular fibrosis, but a limited role in overall organ fibrosis. They discuss the hypothesis that each fibrogenic cell population in the liver exerts specific functions, and whether cell type-specific antifibrotic strategies are required or whether one therapeutic strategy fits all.