Rational antimicrobial administration is still considered to be the most effective therapeutic approach in cystic fibrosis (CF), and long-term treatment with azithromycin (Az) is included in the current guidelines for CF patients aged ≥ 6 years. Az has microbiological, immunomodulatory and anti-inflammatory properties that can reduce some of the biological problems that are among the causes of the progressive lung damage associated with CF. Moreover, although it is not active against Pseudomonas aeruginosa (the most important bacterial pathogen responsible for infectious exacerbations), it can be efficiently used in the case of P. aeruginosa infections because sub-inhibitory concentrations can reduce their pathogenic role by interfering with some bacterial activities and increasing their susceptibility to antibiotics. Az also has anti-viral activity that limits the risk of the bacterial pulmonary exacerbations that frequently occur after apparently mild viral infections. The available data seem to indicate that it is effective during its first year of administration, but the impact of longer treatment is debated. Other still undefined aspects of the use of Az include the possible emergence of antibiotic resistance in the other bacterial pathogens that usually colonise CF patients, the real incidence of adverse events and the drug's potential interference with other routine therapies.