Bisphosphonates are antiresorptive medications widely prescribed for treating osteoporosis. In placebo-controlled clinical trials they have been shown to significantly reduce the risk of osteoporotic fractures. However, reports of atypical femoral fractures and osteonecrosis of the jaw have emerged with long-term use, raising questions regarding their long-term safety. Additionally, questions have also emerged regarding the association between bisphosphonates and other rare adverse events, such as esophageal cancer and atrial fibrillation. This article summarizes the current knowledge regarding the major side effects associated with the use of bisphosphonates, identifies at-risk populations for these side effects, and provides guidance for their use.