The hallmark pathological features of bone disease in patients with cystic fibrosis (CF) include bone micro architectural changes and chronic inflammation which are associated with an irreversible loss in bone strength and density that tracks from childhood to adulthood. Given the equal importance of inflammation and CFTR-related remodeling in bone pathogenesis, there is a significant disparity in studies undertaken to investigate the contribution of each. Up to now, the majority focus on the role of systemic and lung inflammation, and although novel therapeutics such as improved pulmonary function and inflammation have arisen, it is apparent that targeting inflammation alone has not allowed amelioration of cystic fibrosis-related bone disease (CFBD). Therefore, unless bone remodeling is addressed for future therapeutic strategies, it is unlikely that we will progress towards a cure for bone disease. Having acknowledged these limitations, the focus of this review is to highlight the gaps in our current knowledge about the mechanisms underlying CFTR-related bone remodeling, the relationships between inflammation, bone remodeling and clinical phenotypes, and the importance of utilizing innovative pre-clinical models to uncover effective, diseasemodifying therapeutic strategies.