Pulmonary disease remains the primary cause of morbidity and mortality in cystic fibrosis (CF) patients. CF patients develop bronchopulmonary disease at differing ages, but infections with bacterial pathogens initiate a pathophysiological cascade that leads to progressive and irreversible deterioration of lung tissue [1]. Affected individuals consistently maintain high bacterial loads in their airways during periods of clinical stability, punctuated by episodes of pulmonary exacerbation. These pulmonary exacerbations are a hallmark of CF lung disease, and are clinically important because they have an impact on the rate of decline in lung function, survival, quality of life, and healthcare expenditures for patients with CF. They are characterized by an overt immunological response, and are often associated with the acquisition of new microorganisms and the necessity for hospitalization [2]. Standard clinical microbiology assessment of infections that are present during exacerbations often fails to provide any indications of the microbial causes that may drive these perturbations. Culture-based and molecular approaches have established that airway infections are polymicrobial, including previously unrecognized but clinically relevant organisms. This review article will discuss the advances in our understanding of the complexity of the CF microbiome and its implications for disease progression and management.