Bone margin analysis in cases of osteomyelitis, osteoradionecrosis, and medication-related osteonecrosis of the jaw is a controversial topic. There is little evidence to guide treatment and the interpretation of bone margin results. This article examines the significance of margin status and any possible effect on progression of the disease process. A review of various treatment adjuncts used for intraoperative margin analysis during removal of affected tissue is provided. Literature on the role of imaging is also discussed with regards to treatment planning for surgical resection. The histology of the three separate entities including the approach to surgical and pathologic evaluation of margins is also discussed.