More than half of the patients with cystic fibrosis (CF) are infected with Pseudomonas aeruginosa in their lungs. It was thought that patients acquired unique strains of this bacterium from the environment, however in the last decades epidemic clones have been described in other countries that are most likely transmitted between CF patients. Infection with these epidemic clones has been associated with worse clinical outcome. To prevent transmission of such clones a strict segregation policy was implemented in the Netherlands without extensive knowledge of the local epidemiology. CF patients are advised not to meet, are isolated from other patients when visiting the out-patient clinic or when hospitalized and events like summer camps were discontinued. This thesis describes the population structure of P. aeruginosa as highly diverse and highly specific for different patient populations. In CF patients two dominant genotypes are described, ST406 and ST497, that are associated with specific age groups and are different from the epidemic genotypes found abroad. The epidemic strains described abroad are not found in Dutch CF patients. ST406 is harbored by 50% of CF patients between 15 and 25 years of age in 2007 and ST497 was detected mainly in older CF patients. ST406 is not associated with worse clinical outcome, but appears resistant to more antibiotic classes than unique strains and is associated with more inhaled antibiotic therapy. High persistence and possibly ease of transmission seem to have contributed to its spread. Investigating the genome, transcriptome and phenotypic features of two ST406 strains cultured from the same patient with three years in between demonstrated that ST406 is a slow growing, low virulent strain and adaptation to the CF lung niche was driven mostly by point mutations that coincided with differences in transcriptome levels and phenotypic changes, most notably with differences in biofilm formation. Some of the adaptations found in ST406 were also described for other chronic CF ...