Osteoclast differentiation and activity are primarily promoted and regulated via a receptor on osteoclast lineage cells called receptor activator of nuclear factor-kappa B (RANK), which is activated through binding to its only known ligand, RANK ligand (RANKL). Several common diseases presenting with excessive bone loss, such as osteoporosis, osteolytic bone metastases, and rheumatoid arthritis, are characterized by increased RANKL activity. The development and approval of denosumab, a fully human monoclonal antibody against RANKL that inhibits bone resorption in a potent, targeted, and reversible manner, represents a major advance in the treatment of bone diseases. This chapter summarizes the molecular and cellular biology of the RANKL/RANK pathway and reviews preclinical and clinical studies that highlight the efficacy and safety of denosumab and other RANKL inhibitors for the treatment of metabolic and malignant bone diseases.