Ventilator-associated pneumonia (VAP) is the most frequent nosocomial infection in the intensive care unit (ICU), with an incidence ranging from 8% to 38%. Patients who acquire VAP have higher mortality rates and longer ICU and hospital stays. Because there are other potential causes of fever, leukocytosis, and pulmonary infiltrates, clinical diagnosis of VAP is overly sensitive. The only alternative approach to the clinical diagnosis of VAP is the Clinical Pulmonary Infection Score (CPIS). Employing quantitative cultures of respiratory secretions in the diagnosis of VAP leads to less antibiotic use and probably to lower mortality. With respect to microbiologic diagnosis, however, it is not clear that the use of invasive sampling using bronchoscopy is associated with better outcomes. Delayed administration of antibiotic therapy is associated with an increased mortality, and inadequate antibiotic therapy is also associated with higher mortality. Therefore, prompt initiation of adequate antibiotic therapy is a cornerstone of the treatment of VAP. The initial antibiotic therapy should be based on the most common organisms in each hospital and the most likely pathogens for that specific patient. When final cultures and susceptibilities are available, de-escalation to less broad spectrum antibiotics should be done. Since clinical improvement usually takes 2 to 3 days, clinical responses to the initial empirical therapy should be evaluated by day 3. A short course of antibiotic therapy appears to be equivalent to a traditional course of more than 14 days, except when treating non-fermenting gram-negative organisms. If patients receive initially adequate antibiotic therapy, efforts should be made to shorten the duration of therapy to as short as 7 days, provided that the etiologic pathogen is not a non-fermenting gram-negative organism.