Respiratory failure secondary to chronic bronchiectasis is the cause of death in more than 90% of patients with cystic fibrosis (CF). The predominant microbes involved in CF lung disease are unusual: Pseudomonas aeruginosa, Staphylococcus aureus and Burkolderia cepacia. While antimicrobial therapy has been a component of CF care programs for decades, randomized controlled studies in the 1980s and early 1990s failed to show consistent measurable benefit. Research that stemmed from the discovery of the CF gene has shed new light on the inter-relationship of these microbes and the respiratory epithelial lung changes secondary to the CF gene. Five mechanisms have been proposed to explain the increased P aeruginosa colonization of the lower airway in CF. Recent research has also shown that antimicrobial therapy in CF may be effective not through eradication of the organism but by decreasing bacterial density and exoproduct production in the lung and thus decreasing inflammatory stimulus; by protecting against the consequences of an overexhuberant host response and in patients with stop mutations, potentially by correcting the gene defect. This tale of misunderstanding of the role and value of antimicrobial therapy in CF care illustrates the importance of ensuring close communiation between clinicians and researchers. The randomized controlled studies of the 1980s were not designed to answer the ‘right’ questions. The clinicians’ observations that the CF patients did improve with antimicrobial therapy have been validated by recent studies using different endpoints.