Macrolide antibiotics have potent immunomodulatory activity. The spectrum of action of these antibiotics extends to regulation of leukocyte function and production of inflammatory mediators, control of mucus hypersecretion, resolution of inflammation, and modulation of host defense mechanisms. Macrolides are now being used or investigated to treat chronic lung inflammatory diseases, including diffuse panbronchiolitis (DPB), cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD) and asthma. Intense research is ongoing to further elucidate the targets and mechanism/s of action of macrolides in eukaryotic cells. In this paper, we review recent findings on novel effects of macrolides on epithelial barrier function and resolution of inflammation, which may shed light on the mechanisms underlying the beneficial effects of macrolides in the clinic.