Here, we update the current understanding of the physiological and pathophysiological roles mediated by Piezo1 in the musculoskeletal system and discuss why Piezo1 should be regarded as a therapeutic target for musculoskeletal disorders, including osteoporosis (OP), OA, muscle atrophy, and intervertebral disc degeneration (IDD). The gene discussed is PIEZO1; the disease is osteoporosis.