Polymicrobial airway infections are a diagnostic and therapeutic problem for the treatment of patients suffering from cystic fibrosis. Culture-based techniques detect only a fraction of all microbes in the airways. Next generations sequencing approaches now reveal the full microbiome in CF patients' airways. Amplicon-based techniques allow detection of the taxonomic microbiome composition, whereas metagenomic approaches that are currently developed also reveal microbial functions and virulence principles. Cystic fibrosis patients develop dysbiosis, an altered microbiome composition, early in life, first in the nasopharynx and later in the lower airways. Besides well known, culturable pathogenic bacteria, commensal bacteria and anaerobes derived from the oropharynx have been detected in the lower airways. Patients show high inter-individual microbiomes which can be grouped into ecoptypes that show partial correlation with long-term clinical changes. Decrease in lung function and worse development correlate with reduction in microbial diversity within the airways. In contrast, few changes have been observed during exacerbations. In the lower airway anaerobic bacteria can be detected, for which opposing functions, beneficial or detrimental have been reported. As a consequence antibiotic and adjunct therapies will have to be considered with respect to their effects on the microbiome composition.