<p>Fibrosis represents a pathological wound-healing response that occurs after nearly any type of organ injury and has been estimated to lead to half of all deaths in the industrialized world. Current evidence indicates that the extracellular matrix in the fibrotic lesion is primarily produced by activated fibroblasts and/or myofibroblasts. In the liver, the key fibrosis effector cell is the hepatic stellate cell (HSC), which undergoes phenotypic switching from a quiescent (normal) state to a hepatic myofibroblast (activated state). The classic signature for the activated HSC is not only upregulation of various extracellular matrix mRNAs and proteins, particularly type 1 collagen, but also the de novo expression of multiple smooth muscle mRNAs and proteins, including the smooth muscle isoform of actin (smooth muscle α-actin), which supports a robust actin cytoskeleton. Growing evidence indicates that the actin cytoskeleton has a critical role in multiple essential HSC activities during the wound-healing response, including cell migration, contraction, signal transduction and matrix gene expression. In this Review, we focus on the role of the actin cytoskeleton and the molecular processes linking this critically important cellular structure to the cell biology of fibrosis.</p>