Bisphosphonates have been proven to be effective and safe to millions of osteoporotic and cancer patients but were associated with multiple complications. The most prevalent and well established are upper gastrointestinal discomfort for oral bisphosphonates and acute phase reactions for intravenous forms. Although rare, hypocalcaemia and renal injury could be potentially serious. Severe musculoskeletal pain and ocular events may be ignored by physicians, which delay their diagnosis and management. Recently there are growing concerns over two long-term and emerging adverse effects, which are still of unclear pathophysiology and unproven causality. Osteonecrosis of the jaw is more common in cancer sufferers who receive high doses of intravenous bisphosphonates. Atypical femoral fractures are very rare compared with osteoporotic fractures that bisphosphonates prevent. Based on current data, the association of bisphosphonates with esophageal cancer, hepatotoxicity and atrial fibrillation remains doubtful. Overall, the adverse effect profile of these drugs is still unclear. Physicians must be vigilant to bisphosphonate-reported side effects and recognize the level of evidence supporting them, to better communicate the balance between benefits and potential risks to patients.