Pneumonia is a serious complication of mechanical ventilation. Pneumonia occurs despite the best efforts at prevention. Multiple methods available to prevent ventilator-associated pneumonia are reviewed, and ventilation-associated pneumonia (VAP) is divided into early versus late onset. The authors discuss the organisms associated with each of these situations, the empiric antibiotic choices, and specific issues related to antibiotic therapy such as resistance, pharmcodynamics, tissue penetration, and types of modifications necessary in empiric choice when the cause of VAP is identified.