Abstract A key problem in chronic infections is progressive dysfunction of the infected organ. Importantly, patients with similar risk factors often exhibit marked variation in the rate of disease progression, as do individual patients at different times. The chronic Pseudomonas aeruginosa (Pa) lung infections in people with cystic fibrosis (CF) are a prime example. Pronounced variability in the rate of lung function decline is seen across patients even when host CFTR genotype and airway microbiology are similar. While both bacterial and host factors likely contribute to disease variation, several new findings lead us to focus on genetic variation that evolves in infecting Pa. First, CF Pa strains have been found to genetically diversify in vivo, producing clonally-related variants that differ markedly in virulence, and these variants can co-exist simultaneously inside lungs. Second, our data show that the distribution of genetic variants changes over time and the emergence of highly virulent genetic variants can be temporally associated with changes in disease. Finally, many groups have investigated host genetic and environmental factors that affect disease, but the effects of bacterial genetic variants on disease progression are relatively unexplored Here we exploit unique clinical and technical resources, and our knowledge of Pa pathogenesis to test the hypothesis that some gene variants that evolve in the Pa populations infecting CF patients increase lung injury. We will test this hypothesis in three steps. First, will we measure Pa gene variants in sputum collected at specific time points based on the lung disease phenotypes. Second, we will perform genetic association analysis to delineate which variants/variant groups are most strongly associated with the phenotypes. Third, we will investigate the functional effects of gene variants on Pa virulence, host injury, and inflammation. This work could identify potential cause and effect relationships and provide proof of principle for a disease progression mechanism that may operate in many chronic infections.