The binding of cell surface receptors to soluble and insoluble adhesive factors is the principal mechanism by which cells survey their microenvironment and accordingly modulate behaviors such as proliferation, differentiation, migration, and apoptosis. Using microfabrication approaches to engineer cellular microenvironments, we are examining how adhesive and soluble cues cooperate to control basic processes such as endothelial cell proliferation, or the commitment and differentiation of human mesenchymal stem cells to a variety of lineage fates. Here, we describe the approaches we have used to reveal that adhesion appears to exert its effects by modulating mechanochemical signals that regulate actin cytoskeletal tension. This tension appears to be central to driving the lineage commitment process. These studies suggest that mechanical stress generated within cells appears to be a central regulator of cellular function shared among many types of cells.