Purpose of review: Although experimental evidence supports the use of nebulized antibiotics in ventilator-associated pneumonia (VAP), two recent multicenter randomized controlled trials (RCTs) have failed to demonstrate any benefit in VAP caused by Gram-negative bacteria (GNB). This review examines the methodological requirements concerning future RCTs. Recent findings: High doses of nebulized antibiotics are required to reach the infected lung parenchyma. Breath-synchronized nebulizers do not allow delivery of high doses. Mesh nebulizers perform better than jet nebulizers. Epithelial lining fluid concentrations do not reflect interstitial lung concentrations in patients receiving nebulized antibiotics. Specific ventilator settings for optimizing lung deposition require sedation to avoid patient's asynchrony with the ventilator. Summary: Future RCTs should compare a 3-5 day nebulization of amikacin or colistimethate sodium (CMS) to a 7-day intravenous administration of a new cephalosporine/ß-lactamase inhibitor. Inclusion criteria should be a VAP or ventilator-associated tracheobronchitis caused by documented extensive-drug or pandrug resistant GNB. If the GNB remains susceptible to aminoglycosides, nebulized amikacin should be administered at a dose of 40 mg/kg/day. If resistant to aminoglycosides, nebulized CMS should be administered at a dose of 15 millions international units (IU)/day. In VAP caused by pandrug-resistant GNB, 15 millions IU/day nebulized CMS (substitution therapy) should be compared with a 9 millions IU/day intravenous CMS.