Chronic obstructive pulmonary disease (COPD) and other inflammatory airway conditions are major causes of morbidity and mortality worldwide. Antibiotics are used to treat acute infectious exacerbations of airway disease. However, for the macrolides, a significant and growing body of evidence indicates that anti-inflammatory effects of these antibiotics, which may be independent of their antibacterial effects, are at least partially responsible for their beneficial effect. In this review, we describe current thinking on the means whereby anti-inflammatory effects of macrolides impact chronic airway disease. The current data indicate that some macrolides have immunomodulatory activity, mediated at least in part by effects on the activation of gene transcription mediated by NF-__ activation that may be separable from their antimicrobial activities, and could explain their surprising efficacy in asthma and viral infections for which the role of bacteria is not established. Other, provocative work indicates that subclinical doses of macrolides may also affect signalling within and between bacterial communities, and thus impact developmental processes such as biofilm formation that are important in the establishment and persistence of chronic infections. The current data clearly suggest that activities beyond antimicrobial effects contribute significantly to the beneficial effect of macrolide therapy on inflammatory conditions.