The microbiology of the lungs of people with cystic fibrosis (pwCF) is undergoing substantial transformation, driven by advances in CFTR modulator therapy and improved antimicrobial strategies. The traditional paradigm of CF airway infection, centred on opportunistic pathogens such as Pseudomonas aeruginosa and Staphylococcus aureus, is increasingly being replaced by a more complex understanding of polymicrobial airway ecosystems. The interplay between so-called ‘commensals’ and key CF pathogens is likely important to clinical care, but remains poorly understood. Furthermore, the introduction of CFTR therapy has altered the airway microbiome and challenges the clinical relevance of even prominent CF pathogens in the evolving CFTR therapy era. Over the past 15 years, we have characterised the airway microbiome of children and adults with CF using technologies ranging from the PhyloChip and 16S rRNA sequencing to whole-genome shotgun sequencing. We have also developed in vitro assays to investigate polymicrobial interactions within the CF airway microbiome and their potential association with clinical outcomes. The introduction of CFTR therapy in 2019 represented a major milestone in CF care, resulting in substantial reductions in pulmonary exacerbations, decreased bioburden of key pathogens such as P. aeruginosa and overall improvements in health. To better understand the airway microbiome in the context of CFTR modulators, we have followed pwCF receiving elexacaftor/tezacaftor/ivacaftor (ETI) triple therapy from 0-5 years, monitoring clinical status and characterising their airway microbiome using the Illumina NextSeq™ 2000 sequencing platform. A comprehensive understanding of the airway microbiome and microbe–microbe interactions during CFTR therapy will be vital for future CF management.