Cystic fibrosis (CF) is the most common, lethal genetic disease among the Caucasian population. The leading cause of mortality is recurrent acute exacerbations resulting in chronic airway inflammation and subsequent downward progression of pulmonary function. Traditionally, these periods of clinical deterioration have been associated with several principal pathogens. However, a growing body of literature has demonstrated a polymicrobial lower respiratory community compromised of facultative and obligate anaerobes. Despite the understanding of a complex bacterial milieu in CF patient airways, specific roles of anaerobes in disease progression have not been established. In this paper, we first present a brief review of the anaerobic microorganisms that have been identified within CF lower respiratory airways. Next, we discuss the potential contribution of these organisms to CF disease progression, in part by pathogenic potential and also through synergistic interaction with principal pathogens. Finally, we propose a variety of clinical scenarios in which these anaerobic organisms indirectly facilitate principal CF pathogens by modulating host defense and contribute to treatment failure by antibiotic inactivation. These mechanisms may affect patient clinical outcomes and contribute to further disease progression.