Patients with Cystic Fibrosis (CF) are highly susceptible to lung infections caused by different bacteria, among which Pseudomonas aeruginosa (Pa). Phage therapy, namely exploiting phages (bacteria-specific viruses) to kill infecting bacteria, represents a promising strategy for curing bacterial infections refractory to antibiotics in these patients. We assembled a collection of phages able to kill Pa clinical strains isolated from patients with CF and developed a four-phage mixture able to treat Pa infections in animal models. However, the success of phage therapy may be endangered by the appearance of mutant bacteria resistant to phages. The main objective of the project FFC#15/2021 was to understand which bacterial functions are responsible for phage resistance. We found that a single mutation interfering with the biosynthesis of a component of the bacterial cell envelope can confer resistance to the four-phage mixture and identified the functions involved in resistance. Our data suggest possible mechanisms of phage-resistance in Pa clinical strains isolated form patients with CF.  Overall, our results indicate that phage therapy would benefit from a personalized approach, in which phages to be administered to the patient would be chosen based on their ability to kill the specific infecting strain. This requires the generation of a large bank of heterogeneous phages among which fishing the right phages. Phage-resistant mutants isolated or constructed in the frame of this project will be useful tools to assemble such collection.