Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in the ICU. 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 diagnostic criteria are overly sensitive in the diagnosis of VAP. Employing quantitative cultures of bronchopulmonary secretions in the diagnostic algorithm leads to less antibiotic use and probably to lower mortality. With respect to microbiologic diagnosis, it is not clear that the use of a particular sampling method (bronchoscopic or nonbronchoscopic), when quantitatively cultured, is associated with better outcomes. Delayed administration of adequate antibiotic therapy is linked to an increased mortality rate. Hence, the focus of initial antibiotic therapy should be to rapidly provide antibiotic coverage for all likely pathogens and to then narrow or focus the antibiotic spectrum based on the results of quantitative cultures. Eight days of antibiotic therapy appears equivalent to 15 days of therapy except when treating nonlactose-fermenting Gram-negative organisms. In this latter situation, longer treatment durations appear to reduce the risk of recrudescence after discontinuation of antibiotic therapy. A guideline-based approach using the local hospital or ICU antibiogram can increase the likelihood that adequate initial antibiotic therapy is used and reduce the overall use of antibiotics and the associated selection pressure for multidrug-resistant organisms.