Cells perceive mechanical cues in their local environments, which must be converted into intracellular biochemical signals to modulate cellular physiology and control gene expression. This process of mechanical signal transduction (“mechanotransduction”) is critical for development and frequently dysfunctions in disease states such as cancer. Despite increasing appreciation of its importance for human physiology, the molecular mechanisms of mechanotransduction remain poorly understood, hampering efforts to define mechanistically distinct mechanical signaling pathways, delineate their specific biological functions, and target them therapeutically. The actin cytoskeleton, a network of dynamic actin filaments (F-actin), myosin motor proteins, and hundreds of associated factors, enables cells to mechanically interface with their surroundings. While the cytoskeleton is classically understood as a force generation and transmission apparatus that indirectly facilitates mechanotransduction, our research has provided evidence that actin filaments can also serve as direct molecular force transducers. By developing innovative cryo-electron microscopy (cryo-EM) sample preparation and machine-learning based computational analysis approaches, we have uncovered multiple classes of force- dependent structural transitions in F-actin (elicited by fluid flow and myosin molecular motor forces) that can be discriminated by force-sensitive actin-binding proteins. This work has provided a first direct glimpse at how forces alter protein structure to regulate function. Using biophysical reconstitution and cell biology studies, we have also shown how force-activated F-actin binding by proteins from the LIM (LIN-11, Isl-1 & Mec-3) domain superfamily can coordinate downstream mechanotransduction processes, including repair of physical damage to actin- myosin cables mediated by zyxin and extracellular matrix stiffness-dependent nuclear localization of Four-and- a-Half LIM domains (FHL) transcr