Macrolides have broad antibacterial spectrum and proven efficacy in the management of respiratory tract infections. Over the past decade there has been progressive interest in these agents for their potential role as tissue modifying, anti-inflammatory agents. Increasingly, the effect of macrolides on numerous cell types has been documented. Preliminary data have suggested a beneficial clinical role of chronic macrolide therapy in selected patients with chronic rhinosinusitis, chronic obstructive pulmonary disease, cystic fibrosis, non-cystic fibrosis bronchiectasis and asthma. This review presents the biological rationale and the available clinical data of chronic macrolide therapy in chronic respiratory tract diseases. When available, the data addressing the presumed mechanisms underlying clinical benefits are presented.