A breakthrough in antibiotic chemotherapy for patients with chronic Pseudomonas aeruginosa pulmonary infections was brought about by findings in a patient with diffuse panbronchiolitis (DPB), who had been treated with erythromycin over a period of years. Recent clinical trials have demonstrated that long-term macrolide therapy can be used not only for DPB patients but also for those with other chronic infections, including patients with cystic fibrosis (CF). The pathogenesis of chronic P. aeruginosa infection is considered to arise from a bacterial cell-to-cell signaling mechanism, named "quorum-sensing", which enables the bacteria to coordinately turn on and off their virulence genes through the production of autoinducer molecules. Accumulating evidence from clinical and basic science fields suggests the potential of macrolides as Pseudomonas quorum-sensing inhibitors. In this review, we briefly summarize the data on the clinical efficacy of macrolides in DPB and CF patients. Then we discuss the mechanisms of action of macrolides from the viewpoint of sub-minimum inhibitory concentration (sub-MIC) macrolide effects on P. aeruginosa, particularly the potential activity of this antibiotic to suppress the bacterial quorum-sensing system.