The opportunistic pathogen Pseudomonas aeruginosa commonly causes chronic and ultimately deadly lung infections in individuals with the genetic disease cystic fibrosis (CF). P. aeruginosa is metabolically diverse; it displays a remarkable ability to adapt to and successfully occupy almost any niche, including the ecologically complex CF lung. These P. aeruginosa lung infections are a fascinating example of microbial evolution within a “natural” ecosystem. Initially, P. aeruginosa shares the lung niche with a plethora of other microorganisms and is vulnerable to antibiotic challenges. Over time, adaptive evolution leads to certain commonly-observed phenotypic changes within the P. aeruginosa population, some of which render it resistant to antibiotics and apparently help it to out-compete the other species that co-habit the airways. Improving genomics techniques continue to elucidate the evolutionary mechanisms of P. aeruginosa within the CF lung and will hopefully identify new vulnerabilities in this robust and versatile pathogen.