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Comprehending the pathogenesis of giant cell tumor of bone (GCT) is of critical importance for developing novel targeted treatments for this locally-aggressive primary bone tumor. GCT is characterized by the presence of large multinucleated osteoclast-like giant cells distributed amongst mononuclear spindle-like stromal cells and other monocytes. The giant cells are principally responsible for the extensive bone resorption by the tumor. However, the spindle-like stromal cells chiefly direct the pathology of the tumor by recruiting monocytes and promoting their fusion into giant cells. The stromal cells also enhance the resorptive ability of the giant cells. This review encompasses many of the attributes of GCT, including the process of giant cell formation and the mechanisms of bone resorption. The significance of the receptor activator of nuclear factor-κB ligand (RANKL) in the development of GCT and the importance of …