Cells receive mechanical cues via mechanosensitive proteins at the cell membrane–cytoskeletal cortex interface (e.g., PIEZO1/2), as well as cell-cell and cell-matrix adhesions, with cadherins and integrins being the most common mechanical signaling interfaces. Mechanical signal processing occurs through adhesion protein clustering, stabilization of protein-protein interactions (e.g., integrin-talin), and activation of biochemical and transcriptional signaling pathways. These signals may initiate at cell-cell or cell-matrix adhesion sites, or as a consequence of cytoskeletal remodeling (actin, myosin, Rho/ROCK) within the cytoplasm. Cytoskeletal remodeling can also transmit forces across the nuclear envelope (nesprins, lamins), potentially directly altering the environment for transcription. The combination of forces directly transmitted to the nucleus and the nuclear localization of mechanoactivated transcriptional regulators combine with a variety of epigenetic mechanisms to transiently or persistently alter cellular programs that drive injury, repair, and fibrosis responses.