Medication-related osteonecrosis of the jaw (MRONJ) has emerged as a complication of anti-resorptive medications. Despite its low incidence rate, this problem has gained attention in recent years due to its devastating consequences and lack of preventive strategy. The fact that MRONJ incidence has been exclusive to the jawbones, despite the systemic effect of anti-resorptive medications, could be a starting point to unravel the multifactorial pathogenesis of this condition. This review aims to negotiate the question of why the jawbone is more susceptible to MRONJ than other skeletal sites. Approaching the problem from this perspective could provide new directions for the prevention of MRONJ and expand our understanding of the unique oral microenvironment.