BONE IS permanently turned over by the balanced and coordinated action of bone-resorbing osteoclasts and bone-forming osteoblasts, resulting in continuous renewal, functional response to external and internal stimuli, and structural integrity (1–3). Inappropriate bone resorption caused by enhanced osteoclast formation and activity has been previously implicated in the pathogenesis of many metabolic bone diseases. Strategies to inhibit bone resorption have emerged as potent and promising tools for the prevention and treatment of bone and mineral disorders (1–3). The recent discovery and characterization of a novel cytokine system, the tumor necrosis factor (TNF) ligand family member, receptor activator of nuclear factor-κB ligand (RANKL/OPGL/ODF/TRANCE)(4–7); 1 its receptor, receptor activa-tor of nuclear factor κB (RANK/ODAR)(7); and its soluble (decoy) receptor, osteoprotegerin (OPG/OCIF/TR1)(8–11), has established a novel paradigm of osteoclast biology: RANKL, RANK, and OPG constitute the three essential regulatory components of osteoclast formation, fusion, survival, activation, and apoptosis (12–14). This article2 reviews the molecular aspects of this novel cytokine system and its regulation and modulation by various osteotropic agents. Moreover, we summarize the implications of this cytokine system on the pathogenesis of various bone diseases and discuss the therapeutic potential of OPG in the clinical setting.