Bisphosphonates reduce the risk of major osteoporotic fractures and are the most commonly used medications for the prevention and treatment of osteoporosis. Although these medications are well tolerated and safe during large-scale clinical trials, several rare and serious adverse events are suspected to be associated with long-term bisphosphonate use. These adverse events include osteonecrosis of the jaw, atypical fractures, and esophageal cancer. This review summarizes studies examining the association between bisphosphonate use and these adverse outcomes, with a focus on large case series and controlled epidemiologic studies. © 2011 Elsevier Inc.