Musculoskeletal manifestations of transthyretin amyloidosis (ATTR) are common, early in the disease course (usually years before cardiac involvement), and are potentially predictive. They include carpal tunnel syndrome (CTS), trigger finger, atraumatic tears of the brachial biceps tendon or rotator cuff, spinal stenosis, and large joint osteoarthritis. These extra-cardiac ‘red flags’ for ATTR amyloidosis may present individually or in clusters, particularly in older males, several years in advance of signs of ATTR cardiomyopathy (ATTR-CM), such as arrhythmia or heart failure. Deposition of ATTR in the heart leads to severe, often fatal, ATTR-CM that can now be effectively treated. Available treatments slow amyloid fiber deposition but do not allow fiber removal, making early diagnosis and early treatment crucial to improve prognosis. Orthopedists’ and rheumatologists’ knowledge, recognition, and participation in the diagnostic pathway of amyloidosis-related musculoskeletal conditions may help increase suspicion, facilitate early diagnosis, allowing prompt disease-modifying treatment, improving patient outcomes. If surgical intervention is required in patients with these red flags, tissue biopsy at the time of surgery may allow early diagnosis of ATTR deposition, followed by cardiologic screening and/or patient referral to amyloidosis specialty centers if amyloid deposition is evident in biopsy findings. To improve awareness among orthopedic and rheumatology specialists, this narrative review summarizes the published literature on musculoskeletal disorders associated with ATTR amyloidosis, presents relevant diagnostic pathways and indications for histologic examination to facilitate identification of at-risk patients among large numbers of patients, and suggests appropriate follow-up approaches for patients in whom amyloidosis is detected during musculoskeletal surgical procedures.