Epithelial injury and remodeling is common features of several lung diseases such as cystic fibrosis, COPD, acute lung injury and asthma. In cystic fibrosis (CF), mutations in the Cftr gene lead to bacterial colonization and chronic inflammation, causing the progressive damage of the airways, which remains the main cause of morbidity and mortality. Our histological analysis indeed revealed extended areas of epithelial shedding and remodeling in CF human airways and alveoli. Epithelial injury is a deleterious component of the CF pathology, since it may further impair the defense against pathogens, thus creating a vicious circle of infections and injuries. Although repair mechanisms are engaged after damage to restore the epithelial integrity, these processes are obviously insufficient to maintain lung function in CF patients. Our aim was thus to better understand the mechanisms that could impact epithelial wound repair in CF and to develop new therapeutic strategies promoting airway epithelial regeneration. We first demonstrated that alveolar and airway repair processes (including cell migration, proliferation and wound healing) are dependent on K+ channel function coupled to EGF/EGFR signaling as well as to integrin proteins. Indeed, KATP, KCa3.1 and KvLQT1 inhibition reduced epithelial repair rates after EGF or integrin stimulation, whereas K+ channel activation promoted wound healing. Our results indicated that Cl- transport, through CFTR channels, is also crucial for airway epithelial repair. Indeed, we found that CFTR inhibition or silencing in primary human airway epithelial cell monolayers significantly slowed the repair processes. Furthermore, our data revealed a delay in CF bronchial repair compared to non-CF, even in absence of infection. Thus, the basic defect of CFTR could be responsible, at least in part, of the inefficient epithelial regeneration in CF. Moreover, our experiments indicated that the presence of exo-products from Pseudomonas aeruginosa bacteria further decreased the repair capacity of CF primary airway cells. Interestingly, we then discovered that CFTR correction, after wt-CFTR transduction or rescue with CFTR correctors enhanced the repair capacity of airways monolayers, thus highlighting a new, unsuspected function of CFTR correctors. However, the presence of bacterial infection prevented part of the beneficial effect of correctors on CFTR maturation and improvement of epithelial wound healing. We thus believe that it will be now crucial to define the best CFTR correctors and/or K+ channel activators able to efficiently promote lung epithelial repair in CF, even in the presence of infection.