Physical factors drive evolution and play important roles in motility and attachment as well as in differentiation. As animal cells adhere to survive, they generate force and 'feel' various mechanical features of their surroundings, with mechanosensory mechanisms based in part on force-induced conformational changes. Single-molecule methods for in vitro nano-manipulation, together with new in situ proteomic approaches that exploit mass spectrometry, are helping to identify and characterize the molecules and mechanics of structural transitions within cells and matrices. Given the diversity of cell and molecular responses, networks of biomolecules with conformations and interactions sculpted by force seem more likely than singular mechanosensors. Elaboration of the proteins that unfold and change structure in the extracellular matrix and in cells is needed - particularly with regard to the force-driven kinetics - in order to understand the systems biology of signaling in development, differentiation, and disease.