Chronic rhinosinusitis (CRS) is a multifactorial disease characterized by long-term inflammation of the nasal and sinus passages. Neo-osteogenesis which is a major finding of recalcitrant CRS is clinically related to the disease severity and surgical outcomes of CRS.The immunological and molecular mechanisms underlying neo-osteogenesis of CRS remain unclear, and many recent studies have suggested the importance of inflammatory mediators secreted by immune cells. This paper provides a broader understanding of neo-osteogenesis in CRS by reviewing recent updates and evidence of the association between CRS pathophysiology and neo-osteogenesis.Crosstalk between the bone and mucosa eventually results in refractory CRS. In addition, both eosinophilic and non-eosinophilic CRS cytokines can play a role in neo-osteogenesis and trigger an enhanced CRS-associated immune response. The significance of predicting neo-osteogenesis in advance or during postoperative care could be essential for effectively managing refractory CRS and enhancing the prognosis of CRS patients.