Denosumab is an investigational fully human monoclonal antibody to receptor activator of nuclear factor kappaB ligand, an essential mediator of osteoclastic bone resorption. Receptor activator of nuclear factor kappaB ligand plays a major role in the pathogenesis of postmenopausal osteoporosis, structural damage in rheumatoid arthritis, and bone loss associated with other skeletal disorders. This is a review of recent clinical data on the efficacy and safety of denosumab for the treatment of postmenopausal osteoporosis and rheumatoid arthritis.Denosumab reduces bone turnover markers and increases bone mineral density in postmenopausal women with low bone mineral density, reduces fracture risk in women with postmenopausal osteoporosis, and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment. In postmenopausal women with low bone mineral density, denosumab is associated with a greater increase in bone mineral density and greater reduction in bone turnover markers compared with alendronate; when women treated with alendronate are switched to denosumab, there is an increase in bone mineral density that is greater than in those continuing alendronate. Adverse events and serious adverse events, including infections and malignancy, are generally similar in patients treated with denosumab compared with those receiving placebo or alendronate.Denosumab is a promising therapeutic agent for the management of postmenopausal osteoporosis and rheumatoid arthritis.