Many cell types respond to forces as acutely as they do to chemical stimuli, but the mechanisms by which cells sense mechanical stimuli and how these factors alter cellular structure and function in vivo are far less explored than those triggered by chemical ligands. Forces arise both from effects outside the cell and from mechanochemical reactions within the cell that generate stresses on the surface to which the cells adhere. Several recent reviews have summarized how externally applied forces may trigger a cellular response (Silver FH and Siperko LM. Crit Rev Biomed Eng 31: 255-331, 2003; Estes BT, Gimble JM, and Guilak F. Curr Top Dev Biol 60: 91-126, 2004; Janmey PA and Weitz DA. Trends Biochem Sci 29: 364-370, 2004). The purpose of this review is to examine the information available in the current literature describing the relationship between a cell and the rigidity of the matrix on which it resides. We will review recent studies and techniques that focus on substrate compliance as a major variable in cell culture studies. We will discuss the specificity of cell response to stiffness and discuss how this may be important in particular tissue systems. We will attempt to link the mechanoresponse to real pathological states and speculate on the possible biological significance of mechanosensing.