As opposed to acute respiratory infections, the persistent bacterial infections of the lung that characterize cystic fibrosis (CF) provide ample time for bacteria to evolve and adapt. The process of adaptation is recorded in mutations that accumulate over time in the genomes of the infecting bacteria. Some of these mutations lead to obvious phenotypic differences such as antibiotic resistance or the well-known mucoid phenotype of Pseudomonas aeruginosa. Other mutations may be just as important but harder to detect such as increased mutation rates, cell surface changes, and shifts in metabolism and nutrient acquisition. Remarkably, many of the adaptations occur again and again in different patients, signaling that bacteria are adapting to solve specific challenges in the CF respiratory tract. This parallel evolution even extends across distinct bacterial species. This review addresses the bacterial systems that are known to change in long-term CF infections with a special emphasis on cross-species comparisons. Consideration is given to how adaptation may impact health in CF, and the possible evolutionary mechanisms that lead to the repeated parallel adaptations.