Cell adhesion to adsorbed extracellular matrix proteins and adhesive sequences engineered on synthetic surfaces plays a critical role in numerous biomaterial, tissue engineering, and biotechnological applications. Cell adhesion to adhesive motifs is primarily mediated by integrin adhesion receptors. In addition to anchoring cells, supporting cell spreading and migration, integrins provide signals that direct cell survival, proliferation, and differentiation. We have developed two biomolecular strategies for the engineering of surfaces to control integrin binding and cell adhesion in order to direct cell function. The first approach focuses on surfaces presenting well-defined chemistries that control protein adsorption to modulate integrin binding in order to potentiate cell adhesion and signaling thereby directing cell differentiation. In a second approach, we have engineered fibronectin- and collagen-mimetic surfaces presenting controlled ligand densities in a non-fouling background that promote the binding of specific integrin receptors and direct adhesive interactions. These surface engineering strategies provide a basis for the rational design of robust biospecific surfaces that tailor adhesive interactions and elicit specific cellular responses for the development of bioactive implant surfaces, 3D hybrid scaffolds for enhanced tissue reconstruction, and growth supports for enhanced cellular activities.