Matrix stiffness (resistance to deformation), one of the many mechanical forces acting on cells, is increasingly appreciated as an important mediator of cell behavior. It regulates cell signaling broadly, with effects on growth, survival, and motility. Although the stiffness optima for different kinds of adherent cells vary widely, it is generally true that cell proliferation and differentiation increase with the stiffness of the matrix. This review summarizes recent data exploring the nature of matrix stiffness, mechanotransducers, and the many effects of changes in stiffness on cell function. Particular mention is made of data suggesting that cells of the liver are mechanosensitive, highlighting the potential importance of these findings in understanding the biology of normal and diseased liver. (HEPATOLOGY 2008.)