Osteonecrosis of the jaw (ONJ), defined as an oral soft tissue defect with superficial necrosis of the underlying exposed bone, is a severe but uncommon side effect of bisphosphonates (BP). ONJ typically follows a mucosal injury, such as a dental extraction. The exact incidence is unknown but seems to range between 3 and 4%. ONJ occurs after a median of 4 years of “continuous” BP use. There is no specific therapy and 60% of the patients will heal spontaneously in 6–9 months. It seems reasonable to stop BP once ONJ develops until the mucosal lesions heal and then restart BP if clinically indicated; stopping BP before dental procedures is recommended. The use of pamidronate rather than zoledronic acid and less frequent infusions 3-monthly after the first 2 years of monthly infusions may decrease the risk of ONJ, although definitive data are absent. Implementation of preventative measures such as good dental hygiene and limiting the invasiveness of dental procedures seems to decrease the risk of ONJ. Pathogenesis of BP-induced ONJ is unknown. In this chapter, the incidence and risks of ONJ, the clinical presentation, diagnostic workup will be reviewed followed by a summary of the current hypotheses of pathogenesis.