Cells sense biochemical, electrical, and mechanical cues in their environment that affect their differentiation and behavior. Unlike biochemical and electrical signals, mechanical signals can propagate without the diffusion of proteins or ions; instead, forces are transmitted through mechanically stiff structures, flowing, for example, through cytoskeletal elements such as microtubules or filamentous actin. The molecular details underlying how cells respond to force are only beginning to be understood. Here we review tools for probing force-sensitive proteins and highlight several examples in which forces are transmitted, routed, and sensed by proteins in cells. We suggest that local unfolding and tension-dependent removal of autoinhibitory domains are common features in force-sensitive proteins and that force-sensitive proteins may be commonplace wherever forces are transmitted between and within cells. Because mechanical forces are inherent in the cellular environment, force is a signal that cells must take advantage of to maintain homeostasis and carry out their functions.