The beneficial effect of long-term treatment with macrolides in patients with diffuse panbronchiolitis has raised interest in the use of these antibiotics in other chronic inflammatory airway diseases. Recent clinical trials have provided new evidence for a possible role of macrolides in the treatment of airway diseases related to their potential immunomodulatory and anti-inflammatory properties. Macrolides have been shown to reduce the incidence of exacerbations in patients with severe chronic obstructive pulmonary disease (COPD) and frequent exacerbations. In the treatment of idiopathic bronchiectasis, macrolide administration is associated with a reduction in sputum volume and decreased frequency and intensity of exacerbations. Conversely, current evidence is insufficient to support the use of macrolides in the treatment of asthma, although a specific subgroup of patients with refractory asthma and neutrophilic inflammation may derive some benefit. Finally, long-term prophylactic therapy with macrolides may be beneficial for lung transplant recipients, as recent evidence indicates that macrolides are effective in lowering the incidence of bronchiolitis obliterans (BO). This is a review of current evidence on the potential clinical use of macrolides in the long-term treatment of inflammatory airway disorders.