Denosumab, a human monoclonal antibody that inhibits bone resorption by binding on the receptor activator of the nuclear factor kappa-β ligand, has recently emerged as an additional option in the treatment of musculoskeletal osteolytic tumors. This article focuses on the recent literature regarding the effectiveness of denosumab in the management of giant cell tumor, multiple myeloma, aneurysmal bone cyst, and osteosarcoma. The mechanism of action of denosumab in the management of these tumors and the associated side effects are discussed in detail. [ Orthopedics. 2017; 40(4):204-210.].