Bisphosphonates, potent anti-osteoclastic agents, are nowadays the first-line therapy for Paget's disease of bone. Solid evidence about efficacy and the risk/benefit ratio favor tiludronate and risedronate for oral administration and pamidronate for intravenous administration. Treatment is always intermittent, with the frequency of therapeutic sequences depending on the specific drug and the quality and duration of response. Treatment response is assessed by the extent of the reduction of biochemical markers of bone turnover, especially plasma total alkaline phosphatase. The goal of the treatment is to induce full remission, that is, normal levels of alkaline phosphatase. Bisphosphonates should be used in all patients with bone involvement that might create long-term articular (arthropathy) or neurologic (compression) complications. This aggressive strategy is the most likely to provide effective prevention of complications in the long term.