Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in the intensive care unit and is associated with major morbidity and attributable mortality. Strategies to prevent VAP are likely to be successful only if based upon a sound understanding of pathogenesis and epidemiology. The major route for acquiring endemic VAP is oropharyngeal colonization by the endogenous flora or by pathogens acquired exogenously from the intensive care unit environment, especially the hands or apparel of health-care workers, contaminated respiratory equipment, hospital water, or air. The stomach represents a potential site of secondary colonization and reservoir of nosocomial Gram-negative bacilli. Endotracheal-tube biofilm formation may play a contributory role in sustaining tracheal colonization and also have an important role in late-onset VAP caused by resistant organisms. Aspiration of microbe-laden oropharyngeal, gastric, or tracheal secretions around the cuffed endotracheal tube into the normally sterile lower respiratory tract results in most cases of endemic VAP. In contrast, epidemic VAP is most often caused by contamination of respiratory therapy equipment, bronchoscopes, medical aerosols, water (eg, Legionella) or air (eg, Aspergillus or the severe acute respiratory syndrome virus). Strategies to eradicate oropharyngeal and/or intestinal microbial colonization, such as with chlorhexidine oral care, prophylactic aerosolization of antimicrobials, selective aerodigestive mucosal antimicrobial decontamination, or the use of sucralfate rather than H(2) antagonists for stress ulcer prophylaxis, and measures to prevent aspiration, such as semirecumbent positioning or continuous subglottic suctioning, have all been shown to reduce the risk of VAP. Measures to prevent epidemic VAP include rigorous disinfection of respiratory equipment and bronchoscopes, and infection-control measures to prevent contamination of medical aerosols. Hospital water should be Legionella-free, and high-risk patients, especially those with prolonged granulocytopenia or organ transplants, should be cared for in hospital units with high-efficiency-particulate-arrestor (HEPA) filtered air. Routine surveillance of VAP, to track endemic VAPs and facilitate early detection of outbreaks, is mandatory.