Elucidation of the molecular pathways underlying bone turnover has revealed potential therapeutic targets, including receptor activator of nuclear factor-κB ligand (RANKL), which is a mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody that binds to and inhibits RANKL. This agent has been developed for use in patients with early-stage and advanced-stage cancer, as well as for the treatment of osteoporosis, and can prevent bone loss and reduce fragility fractures in both types of disease. In the bone metastasis setting, several large phase III studies have shown that denosumab is more effective than bisphosphonates, namely zoledronic acid, in reducing skeletal morbidity arising from a wide range of tumors. In addition, a remarkable activity of denosumab has been demonstrated in giant-cell tumors of the bone. Subsequent studies of denosumab have demonstrated that it can delay bone metastasis in patients with castration-resistant prostate cancer; adjuvant studies in patients with breast cancer are in progress. This Review critically explores the emerging role of denosumab in maintaining bone health in the oncology setting, and discusses the factors that are likely to influence the choice between bisphosphonates and denosumab in clinical practice.