Cystic fibrosis (CF) is the most common lethal genetic disease in the Caucasian population, and should be considered an infectious disease because of the basic pathophysiology. Chronic lower airway infections cause a progressive pathologic deterioration of lung tissue, a decline in pulmonary function and, ultimately, respiratory failure and death in 90% of CF patients. Historically, very few bacterial species have been implicated as principal CF pathogens. However, molecular evidence suggests the presence of a diverse mosaic of bacteria in CF lungs, and infections can be defined as polymicrobial. Here we review the work that supports this concept and we discuss the potential significance of the polymicrobial community in lung pathology. Understanding the dynamics of polymicrobial infections, the interplay between pathogen(s), normal oropharyngeal flora and the host immune system may lead to future advances in the therapeutic management of chronic lung infections.