Giant cell-containing tumors of bone are characterized morphologically by the presence of numerous osteoclastic giant cells. Correlation of clinical, radiologic, and laboratory findings is required for accurate histopathologic diagnosis and treatment of a giant cell-containing tumor of bone. In differential diagnosis, it is particularly important to note the age of the patient and the skeletal location of the lesion. This article considers the range of neoplastic and nonneoplastic lesions, which histologically contain numerous osteoclastic giant cells, and focuses on several lesions that frequently enter into the differential diagnosis.