Repeated pulmonary exacerbation and progressive lung function decline characterize cystic fibrosis (CF) disease, and represents one of the leading causes of mortality in this patient population. Recent studies have shown, using culture-independent assays, that multiple microbial species can be detected in airway samples from CF patients. Moreover, specific groups of bacteria within these bacterial communities or microbiota, are highly associated with disease-associated factors such as antibiotic administration. This raises the possibility that, as in other human niches, pathogenic processes in the CF airways represent polymicrobial activities and that microbiome composition and perturbations to these communities define patient pulmonary health status. Airway samples are typically collected through the mouth, and are thus susceptible to contamination by upper airway secretions; hence, caution must be exercised in interpreting these data. Nonetheless, given the continuum of the upper and lower respiratory tract, understanding the contribution of these mixed-species assemblages to airway health is essential to improving CF patient care. This article aims to discuss recent advances in the field of CF airway microbiome research and interpret these findings in the context of CF pulmonary disease.