Osteoprotegerin (OPG)–receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) have been identified as members of a ligand–receptor system that directly regulates osteoclast differentiation and osteolysis. RANKL may be a powerful inducer of bone resorption through its interaction with RANK, and OPG is a soluble decoy receptor that acts as a strong inhibitor of osteoclastic differentiation. Any dysregulation of their respective expression leads to pathological conditions. Furthermore, recent data demonstrate that the OPG–RANK–RANKL system modulates cancer cell migration, thus controlling the development of bone metastases. This review describes the most recent knowledge on the OPG–RANK–RANKL system, its involvement in bone oncology and the new therapeutic approaches based on this molecular triad.