Treatment with a potent bisphosphonate is indicated in patients with Paget's disease who have symptoms likely to respond to reduced bone turnover at pagetic sites. In asymptomatic patients with active disease at sites susceptible to local progression and late complications, treatment is also recommended. Biochemical remission is achievable in a majority of patients with pamidronate, alendronate, risedronate, or zoledronic acid. Indications for medical treatment of active Paget's disease of bone include symptoms referable to sites of the disease such as bone pain, joint pain, and neurological complications; elective surgery at an active pagetic site to reduce intraoperative blood loss from highly vascular bone; management of rare instances of immobilization hypercalcemia with polyostotic disease; and presence of disease activity in asymptomatic patients at sites at risk for future complications to limit progression and possibly lower that risk. The treatment of choice is a potent nitrogen-containing bisphosphonate, including oral alendronate or risedronate or intravenous pamidronate or zoledronic acid. Etidronate and tiludronate are less potent and are second-line choices. Recent data with zoledronic acid indicate that a single infusion of 5 mg is associated with normalization of serum alkaline phosphatase in 89% of patients and a prolonged biochemical remission, making it the most effective therapy available to date. Side effect profiles with alendronate and risedronate include esophageal irritation in a minority of patients. Intravenous pamidronate and zoledronic acid may induce an acute phase reaction with fever and flu-like symptoms with the first dose, primarily in patients who are treatment naïve to nitrogen-containing bisphosphonates. Calcium and vitamin D repletion are mandatory with these potent anti-osteoclast therapies to avoid hypocalcemia. Acquired resistance to etidronate and pamidronate has been reported in some patients, leading to lesser reductions in bone turnover and shorter periods of remission, but substitution with a different bisphosphonate provides a more robust response. It is not known whether resistance to other bisphosphonates in Paget's disease occurs.