We conducted studies using micropatterned substrates to elucidate how cell shape and geometric confinement regulates the inter- and intracellular signaling pathways required for cell motility. When cells were cultured on individual cell-sized square adhesive islands coated with ECM, they extend to the edge of the island and assume a square shape. When these cells were stimulated with growth factors, they preferentially extended lamellipodia from the corners versus the sides. This process was mediated by myosin-generated isometric tension that induced tight spatial localization of Rac in the corners. When two or three capillary endothelial cells are constrained to a fibronectin (FN) island, coordinated cell migration results in stable rotation of the entire system about its center. Thus, the emergent pattern is due to the coordinated migration behavior of the cells. These observations suggest that ECM-induced mechanotransduction potentiates compartmentalized signaling pathways and the multicellular organization required of tissue morphogenesis.