While engineered matrices allow asking well defined questions of how cells interact and respond to their environment, it remains unclear whether a minimal set of cues exists by which synthetic matrices can be engineered that mimics biological matrices in their essential functions. Here we address how mechanical force can alter the conformation of extracellular matrix proteins and consequently regulate the display of the protein's functional states. The function of cells is tightly controlled by their interaction with the surrounding extracellular matrix to which they are coupled via the transmembrane integrins. Using intramolecular fluorescence resonance energy transfer (FRET), we studied the extent to which fibronectin is stretched and partially unfolded by the traction forces generated by fibroblasts in 2d and 3d matrices. We then derive structural models of the unfolding pathways of ECM proteins by computational techniques (steered molecular dynamics simulations), and gain insight how tension applied to extracellular matrix proteins affects the exposure of their molecular recognition sites. The consequences of our findings to the field of biomaterials and tissue engineering will be discussed. @FootnoteText@ V. Vogel, G. Baneyx, The tissue engineering puzzle: a molecular perspective, Annual Review Biomed. Eng., 5 (2003) 441-463. G. Baneyx, L. Baugh, V. Vogel, Co-existing conformations of fibronectin imaged in cell culture by fluorescence resonance energy transfer, Proc. Natl. Acad. Sci. USA, 98 (2001) 14464-14468. G. Baneyx, L. Baugh, V. Vogel, Fibronectin extension and unfolding within cell matrix fibrils controlled by cytoskeletal tension, Proc. Natl. Acad. Sci. USA, 99 (2002) 5139-5143. D. Craig, M. Gao, K. Schulten, V. Vogel, Structural insights how sequence variations tune the mechanical stability of fibronectin type III modules, Structure, 12 (2004) 21-30.