Pseudomonas aeruginosa is a dominant pathogen in people with cystic fibrosis (CF) contributing to morbidity and mortality. Its tremendous ability to adapt greatly facilitates its capacity to cause chronic infections. The adaptability and flexibility of the pathogen are afforded by the extensive number of virulence factors it has at its disposal, providing P. aeruginosa with the facility to tailor its response against the different stressors in the environment. A deep understanding of these virulence mechanisms is crucial for the design of therapeutic strategies and vaccines against this multi-resistant pathogen. Therefore, this review describes the main virulence factors of P. aeruginosa and the adaptations it undergoes to persist in hostile environments such as the CF respiratory tract. The very large P. aeruginosa genome (5 to 7 MB) contributes considerably to its adaptive capacity; consequently, genomic studies have provided significant insights into elucidating P. aeruginosa evolution and its interactions with the host throughout the course of infection.