Giant cell tumor is a relatively uncommon but painful tumor of bone, which can metastasize to the lungs. The RANK pathway is often reported to be involved in the pathogenesis of giant cell tumor of bone (GCTB). This pathway is a key signaling pathway of bone remodeling that plays a critical role in differentiation of precursors into multinucleated osteoclasts, and activation of osteoclasts leading to bone resorption. Dysregulation of RANK ligand (RANKL)-RANK-osteoprotegerin (OPG) signaling cascade induces the imbalance between bone formation and bone resorption, which leads to the changes in bone mass, increases osteoclast-mediated bone destruction, bone metastasis, and the progression of existing skeletal tumors. Recent evidences have shown that targeting the components of RANKL-RANK-OPG signaling pathway is a promising approach in the treatment of GCTB. This review study has focused on the association of RANKL-RANK-OPG pathway in the pathogenesis and progression of GCTB as well as discussed the possible therapeutic strategies by targeting this pathway.