Antimicrobial resistance is arguably the most significant challenge facing the EU health care system. The unnecessary use of antibiotics is a key driver in the development of antibiotic resistance. Cystic Fibrosis (CF) represents a unique disease model to study bacterial resistance and to explore therapeutic strategies for same, as chronic lung infection overlaps with acute lung exacerbations caused by a multitude of organisms that traditionally evolve various mechanisms of resistance. With time, chronic polymicrobial infection develops, with the most dominant infecting organism being Pseudomonas aeruginosa, which is also important in other infections including wounds, burns and patients with medical devices, making it an important clinical target for the EU. In CF infections, empiric intravenous antibiotics are usually given for two weeks. Recurrent infections and treatments result in increasing antimicrobial resistance, and alterations in pathogen host interactions in the lung and gut flora. Next-generation DNA sequencing technology now offers DNA-based personalised diagnostics and treatment strategies. Enhancing our knowledge of the microbiome allows the use of stratified targeted antibacterial therapy that can be compared with standard empirical antibacterial therapy currently used. We believe this will reduce antibiotic usage, optimize dosage and duration startegies as the therapy will be tailored to the actual individual patient needs. Cystic Fibrosis Microbiome-determined Antimicrobial Therapy Trial in Exacerbations: Results Stratified (CF MATTERS) will provide a randomized multi-centre controlled trial of microbiome-derived antimicrobial treatments versus current empirical therapy. Simultaneously parallel human host-pathogen interaction studies in sputa, human gut microflora analysis and evaluation of murine exacerbation models will be performed. This will improve prescription practice and decrease antimicrobial usage and resistance.