Giant cell tumor of bone is an enigmatic osseous neoplasm that is histologically benign but clinically shows local aggression and metastatic potential. The absence of clinical, radiographic, or pathologic features that are predictive of tumor behavior and patient outcome has resulted in recent attention to the pathobiology of giant cell tumor of bone. In this report, the clinicopathologic features of and current treatment approaches to giant cell tumor of bone are reviewed. Recent investigations of the specific role of the cell populations present in giant cell tumor of bone that influence tumor proliferation, bone resorption, and its clinical behavior are described.