Cystic fibrosis (CF) is the most frequent inherited disease in Caucasian populations and is due to a defect in the expression or activity of an anion channel encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Many studies have reported a difference in survival between males and females with CF, termed the ‘‘CF gender gap”, showing a decreased median survival of 10 years for women. The precise physiological and molecular mechanisms underlying the CF gender gap are not fully known and although it appears that a gender gap exists before girls reach puberty (1), recent studies have shown the prominent role of the most potent form of estrogen, 17β-estradiol (E2), in exacerbating lung function in CF females. Early cohort studies showed an association between female gender and an earlier median age of chronic lung infection with mucoid Pseudomonas aeruginosa (Psa.) (2). There also exist a stronger association between the age at first Pseudomonas aeruginosa infection and the severity of lung disease in females with CF compared to males (3). These studies suggest that E2 could have an effect on immunity and that has since been confirmed in numerous studies. Injecting CF mice with E2 before infection wits Psa, increased the number of white blood cells in broncho-alveolar lavage and also increased the inflammatory infiltrate and mRNA of various inflammatory mediators. Chotirmall et al. have studied different aspects of the involvement of E2 in the modulation of infection and immunity. They have shown that the female hormone upregulates SLPI, an anti-protease with anti-inflammatory properties, leading to the inhibition of NK-κB, potentially compromising a protective inflammatory process. This group has also shown that E2 induced the transformation of Psa. from a non-mucoid to a mucoid form by inducing the production of alginate. This study also reported a correlation between the levels of plasma E2 and the severity of lung exacerbations in CF females (4). Estrogen can also regulate fluid and ion transport. Indeed, it has been shown in other organs that E2 can inhibit K+ channels involved in the regulation of epithelial repair, therefore, E2 could negatively regulate epithelial wound healing in CF lung, an organ strongly damaged by the cycles of recurring infections and inflammation processes. Moreover, papers from 1998 and 2011 reported that E2 increases Na+ absorption and ENaC activity in alveolar cells (5,6). Our study from 2013 confirmed the existence of the same effect in bronchial epithelial cells and showed that E2 impaired the airway surface liquid (ASL) dynamics by decreasing ASL height through an increase in ENaC and the Na+/K+-ATPase activities. The hyperabsorption of Na+ leads to an increase in Na+ and water absorption through the bronchial epithelium. We demonstrated that the rapid effect of estrogen on ASL height and ENaC involved an extra-nuclear Estrogen Receptor α with similar responses generated by a non-nuclear estrogen dendrimer conjugate that allowed us to discriminate between genomic and non genomic effects of E2 (7). Finally, as survival increases, CF patients are more at risk to develop non-pulmonary CF-related diseases. Some recent studies showed, for example, that in patients with a severe genotype, there are more CF women with CF Related Diabetes than men and diabetes is linked to a decreased survival in CF females. It has also been demonstrated that female CF mice had reduced bone formation rate than their male counterparts. There is now strong evidence from epidemiology, molecular endocrinology and physiological studies that raised plasma levels of estrogen can exacerbate lung pathophysiology and function in CF females as well as affecting other organs. The molecular basis for the CF gender gap involves a compromised innate immune response, combined with impaired airway surface liquid dynamics arising from Na+ hyper-absorption and dehydration of the periciliary layer. In addition, estrogen acts directly on Psa. conversion to a virulent mucoid phenotype and biofilm production, completing a vicious cycle of compromised mucociliary clearance, infection and inflammation.