Amyloidosis comprises a heterogeneous group of diseases in which otherwise normal proteins acquire alternative misfolded states and form insoluble amyloid fibrils. Subsequently, extracellular deposition of amyloid fibrils into various organs and tissues results in infiltration, swelling, and progressive loss of function of the affected organ. Amyloid fibrils deposit either locally or systemically. Diseases in which localized amyloidosis is encountered include Alzheimer disease, type 2 diabetes mellitus, lichen amyloidosis, and nodular and macular amyloid. Unlike localized amyloidosis, the progressive disease course of infiltrated organs and tissues in systemic amyloidosis culminates in significant clinical manifestation. There are four main types of systemic amyloidosis, named according to the dominant associated factor, state or disease process, and, therefore, the underlying precursor protein. The musculoskeletal manifestations of amyloidosis are common and are the primary focus of this chapter. Radiographically, bone lesions of amyloidosis demonstrate variably sized medullary or cortical radiolucencies. The latter is often associated with sclerotic margins and may progress to frank cortical destruction. These lesions are typically periarticular and favor the carpal bones, femoral and humeral heads and necks, acetabulum, tibia plateau, and distal radius. MRI and ultrasonography play a role in the detection of extraosseous deposition of amyloid. On MRI, amyloid deposits show intermediate to low signal due to prolonged T1 and shortened T2 relaxation times. Sonography of the affected wrist may demonstrate thickened flexor and extensor tendons, as well as amyloid deposits in the synovium. The imaging differential diagnosis of amyloidosis includes tenosynovial giant cell tumor (formerly known as pigmented villonodular synovitis (PVNS)), gout, and rheumatoid arthritis. Ultimately, as amyloidosis is a tissue infiltrative process, its definitive diagnosis requires tissue sampling. Treatment of amyloidosis is based on the so-called “precursor-product” concept. Therefore, the aim is to diminish precursor supply, to halt growth of amyloid deposits.