Bone metastases play an important role in the morbidity and mortality of patients with malignant disease. Despite therapeutic advances in the treatment of solid organ malignancy such as lung cancer, less development on metastasis interventions has been forthcoming. More recent research has focused on molecular pathway manipulation in the prevention and treatment of metastatic bone disease and associated complications such as bone pain and hypercalcemia. The osteoprotegerin/receptor activator of nuclear factor-кβ ligand/receptor activator of nuclear factor-кβ pathway, which is physiologically involved in bone turnover, has been of considerable interest, and recent promising data have been revealed. In this study, we describe this molecular pathway in terms of its natural physiological function, manipulation for therapeutic benefit, and recent clinical trial results.