We address the question of whether human airway epithelia have increased Na+ permeability in cystic fibrosis (CF) disease. CF is the most common lethal genetic disease among Caucasians. It is known that loss-of-function mutations in the CFTR gene, encoding an anion channel, cause reduced Cl- permeability in CF airway epithelia, however whether increased epithelial Na+ channel (ENaC) activity also arises in the disease state is an open question. We have focused on elucidating the quantitative relationships between individual transport protein activities (e.g. CFTR and ENaC) and the trans-epithelial potential difference (PD). Our study finds that the observed bioelectric properties of CF human nasal epithelial (HNE) cells can only be explained quantitatively if the loss of Cl- permeability is accompanied by a corresponding increase in apical Na+ permeability. We arrive at this conclusion after developing a biophysically motivated mathematical model which describes the electrical, chemical and osmotic state of the HNE cell during measurement of trans-epithelial PD. Our analysis consists of three stages, first we estimate ionic permeabilities in CF and non-CF HNE cells, by directly fitting model predictions to time series of membrane potentials and intracellular concentrations recorded in primary HNE cell cultures. Then, we investigate the extent to which individual variation in the measured electrophysiological data maps to distributions of ionic permeability values in the normal and disease state. To this end we randomly permute 106 different transport parameter configurations, simulate trans-epithelial recordings in silico and determine which configurations allow acceptable CF and non-CF behaviour. Finally, given the distribution of acceptable parameter sets and predicted electrophysiological data, we perform a multivariate sensitivity analysis, to determine which transport parameters have most influence on the recorded properties of interest, such as the trans-epithelial PD and the amiloride sensitive PD. With these approaches we find that a relative increase in Na+ permeability is necessary to produce the observed differences in bioelectric properties between non-CF and CF airway epithelia, and we find this conclusion holds despite the large variation observed in these electrophysiological properties. The results of our sensitivity analysis show that trans-epithelial PD is relatively insensitive to CFTR permeability, and very sensitive to changes in ENaC permeability, and this gives us the insight into why the apical Na+ permeability must differ in CF, as a loss of Cl- permeability is simply not sufficient to hyperpolarize the trans-epithelial PD to the extent seen in CF.