Osteoprotegerin (OPG)-receptor activator of nuclear factor-kappaB (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.