OPINION STATEMENT: Giant cell tumor of bone (GCTB) comprises up to 20 % of benign bone tumors in the US. GCTB are typically locally aggressive, but metastasize to the lung in ~5 % of cases. Malignant transformation occurs in a small percentage of cases, usually following radiation therapy. Historically, GCTB have been treated primarily with surgery. When the morbidity of surgery would be excessive, radiation therapy may achieve local control. In most cases the primary driver of the malignant cell appears to be a mutation in H3F3A leading to a substitution of Gly34 to either Trp or Leu in Histone H3.3. This change presumably alters the methylation of the protein, and thus, its effect on gene expression. The malignant stromal cells of GCTB secrete RANKL, which recruits osteoclast precursors to the tumor and stimulates their differentiation to osteoclasts. The elucidation of the biology of GCTB led to trials of the anti-RANKL monoclonal antibody denosumab in this disease, with a clear demonstration of beneficial clinical effect. Surgery remains the primary treatment of localized GCTB. When surgery is not possible or would be associated with excessive morbidity, denosumab is a good treatment option. The optimal length of treatment and schedule of denosumab is unknown, but recurrences after apparent complete responses have been observed after stopping denosumab, and long-term follow-up of denosumab treatment may reveal unrecognized effects. The role of denosumab in the preoperative or adjuvant setting will require clinical trials. In some cases local radiation therapy may be useful, although long term effects should be considered.