While the effects of extracellular matrix chemistry have been well-studied, the role of substrate mechanics has only recently become of an area of intense interest. It is now well-known that substrate mechanics can alter many fundamental cell functions including cell adhesion, migration, contractility and gene expression. Using well-defined deformable substrates, we have recently found that cells can communicate mechanically through compliant substrates by exerting traction stresses that alter the strain field beneath adjacent cells. This exchange of mechanical information draws cells together and increases the stability of cell-cell adhesion between communicating cells. On softer substrates, where cells are less spread, cells tend to adhere to each other whereas on stiffer substrates, cells prefer to adhere and migrate on the substrate. We have recently extended these studies to explore the synergistic effects of substrate compliance and chemistry on the balance between cell-cell and cell-matrix adhesion. Our results indicate that decreasing the strength of cell-matrix adhesion by altering substrate mechanics or chemistry increases the stability of cell-cell adhesion. These changes in cell-cell adhesion result in increased endothelial cell aggregation and the formation of cellular networks. Our data underscore the importance of substrate mechanics in mediating the balance between cell-cell and cell-matrix adhesion and help to define material parameters that can enhance tissue formation on well-controlled biomaterial surfaces.