Bisphosphonates (BPs) represent the most widely used therapy for osteoporosis. Recently, a relationship between long-term treatment with BPs and a subset of atypical femoral fractures (AFFs) from below the lesser trochanter to the sovracondilar line has been described. Many etiopathogenetic theories have been invoked to explain AFFs: reduced bone turnover and increased osteoblast bone apposition with accumulation of microdamage and decreased bone toughness with subsequent increased risk of micro-cracks and duration fractures, collagen fiber cross-linking and vascularization impairment. Based on published studies, a task force of the American Society for Bone and Mineral Research has redacted the diagnostic criteria of AFFs by classifying them according to their major and minor criteria. The treatment for displaced AFFs is osteosynthesis, but there is a lack of evidence for undisplaced AFFs and the duration of fracture treatment. BPs have a proven efficacy in osteoporotic fracture reduction as well as in the treatment of other bone diseases caused by the downregulation of osteoclast activity. BPs have an excellent benefit-to-risk ratio; however, minor adverse events, such as AFFs, occur in a variable percentage of patients treated over a long period of time.