The cystic fibrosis (CF) lung is chronically inflamed and infected by Pseudomonas aeruginosa, which is a major cause of morbidity and mortality in this genetic disease. Although aerosolization of Tobramycin into the airway of CF patients improves outcomes, the lungs of CF patients, even those receiving antibiotic therapy, are persistently colonized by P. aeruginosa. Recent studies suggest that the antibiotic resistance of P. aeruginosa in the CF lung is due to the formation of drug resistant biofilms, which are defined as communities of microbes associated with surfaces or interfaces, and whose growth is facilitated by thick and dehydrated mucus in the CF lung. In this review, we discuss some of the current models used to study biofilm formation in the context of biotic surfaces, such as airway cells, as well as the contribution of host-derived factors, including DNA, actin and mucus, to the formation of these microbial communities. We suggest that better in vitro models are required, both to understand the interaction of P. aeruginosa with the host airway, and as models to validate new therapeutics, whether targeted at bacteria or host.