Cells need to be anchored to extracellular matrix (ECM) to survive, yet the role of ECM in guiding developmental processes, tissue homeostasis, and aging has long been underestimated. How ECM orchestrates the deterioration of healthy to pathological tissues, including fibrosis and cancer, also remains poorly understood. Inquiring how alterations in ECM fiber tension might drive these processes is timely, as mechanobiology is a rapidly growing field, and many novel mechanisms behind the mechanical forces that can regulate protein, cell, and tissue functions have recently been deciphered. The goal of this article is to review how forces can switch protein functions, and thus cell signaling, and thereby inspire new approaches to exploit the mechanobiology of ECM in regenerative medicine as well as for diagnostic and therapeutic applications. Some of the mechanochemical switching concepts described here for ECM proteins are more general and apply to intracellular proteins as well.

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