In this article, the authors outline some of the major historical events that signaled the need to better understand mechanisms of infection in cystic fibrosis (CF). The authors discuss general principles of infection control, focusing on issues of particular importance to patients who have CF. The authors also describe the major pathogens associated with the CF airway, provide a review of findings from inpatient and outpatient studies of infection control, and provide an outline of future directions for investigation.