A comprehensive analysis of the airway microbiome in cystic fibrosis (CF) has revealed that the airways are a reservoir of previously unrecognized but clinically relevant organisms. Traditionally, antibiotic intervention in patients with CF presenting with acute bronchopulmonary exacerbations has been directed at a limited number of bacterial pathogens. In patients chronically colonized by conventional pathogens that demonstrate no bacteriological response to standard therapy, other antibiotics may have clinical efficacy. Using a case-based example, this review argues that pathogen-directed treatment based on inclusive quantitative microbiological protocols can result in improved patient outcomes. Furthermore, future therapeutic approaches that may rely on a polymicrobial perspective of the airways in CF are discussed.