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Bisphosphonates (BP), potent osteoclast inhibitors, play a key role in managing patients with osteoporosis, Paget’s disease, bone metastasis, and multiple myeloma. BP’s anti-resorptive activity substantially reduce fracture risk by 40%-70% in osteoporosis patients, and improve quality of life in cancer patients by preventing skeletal complications. However, prolonged BP use is associated with a significant dental complication termed “Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ)”. To date, the true incidence, etiology, and risk factors that contribute to BRONJ pathogenesis are unknown. In this dissertation, we assessed the frequency, etiology and risk factors that contribute to BRONJ pathogenesis. We noted that the BRONJ frequency in cancer patients is around 3.1%. Factors such as poor periodontal status, diabetes, smoking, prolonged duration of BP therapy, and higher numbers of BP infusions significantly increase the risk of developing BRONJ. In addition, long-term BP administration adversely affects jawbone mechanical properties that could result in increased microdamage accumulation within the jaw bones. Furthermore, using proteomic analysis we identified 200 salivary proteins that were differentially expressed in BRONJ subjects. A majority of the differentially expressed proteins were predicted to have a role in dermatological diseases, genetic disorders, immunological diseases, and inflammatory responses. Finally, analysis of serum samples revealed that VEGF levels are significantly suppressed in patients undergoing BP therapy. In summary, results from this dissertation provide insight into the pathogenesis of BRONJ development.