The histological picture of giant cell tumor of bone is characterized by numerous osteoclast-like giant cells. However, these are not the actual tumor cells, but constitute a reactive infiltrate. Rather, the tumor cells are mononuclear mesenchymal cells, which even reveal an osteoblastic line of differentiation. The CD68-positive macrophages form the second group of mononuclear cells. The receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL) system, which belongs to the tumor necrosis factor (TNF) cytokine family, is decisively involved in the activation of the giant cells. It is generally accepted that a RANKL expression of mononuclear stromal cells is responsible for the development and differentiation of osteoclast-like giant cells. Therefore, the RANKL inhibitor denosumab constituted an essential element for giant cell tumor therapy over the last several years, as it blocks the maturation of osteoclasts and thus the osteolytic activity and the spread of tumor. However, with time it became evident that the not risk-free therapy with denosumab may lead to extensive recurrences upon withdrawal, so this therapy is applied with caution today.At the molecular genetic level, the giant cell tumors of bone are characterized by point mutations in the H3F3A gene. The detection of this mutation is used for the diagnostic differentiation from other bone lesions containing giant cells. Giant cell osteosarcomas rarely contain H3F3A mutations. Chondroblastoma is characterized by mutations in the H3F3B gene.