Therapy of ventilator-associated pneumonia should be a patient-based approach focusing on some key features are listed here: early initial therapy should be based on broad-spectrum antibiotics. Empirical treatment may be targeted after direct staining and should be modified according to good-quality quantitative microbiological findings, but should never be withdrawn in presence of negative direct staining or delayed until microbiological results are available. Courses of therapy should be given at high doses according to pharmacodynamic and tissue penetration properties. Prolonging antibiotic treatment does not prevent recurrences. Methicillin-sensitive Staphylococcus aureus should be expected in comatose patients. Methicillin-resistant Staphylococcus aureus should not be expected in patients without previous antibiotic coverage. Pseudomonas aeruginosa should be covered with combination therapy. Antifungal therapy, even when Candida spp is isolated in significant concentrations, is not recommended for intubated nonneutropenic patients. Vancomycin, given at the standard doses and route of administration for the treatment of VAP caused by Gram-positive pathogens, is associated with poor outcomes. The choice of initial antibiotic should be based on the patient's previous antibiotic exposure and comorbidities, and local antibiotic susceptibility patterns, which should be updated regularly.