There is considerable evidence to suggest that specific interventions can be effectively employed to prevent hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). These interventions consist of pharmacological and nonpharmacological strategies that focus on prevention of aerodigestive tract colonization and the prevention of aspiration of contaminated secretions, the major pathogenetic mechanisms leading to HAP. Important components of effective preventive strategies focus on basic infection control principles like handwashing, adequate intensive care unit (ICU) staff education, and optimal resource utilization. Measures to prevent HAP/VAP extend into all aspects of daily intensive care practice, including antibiotic selection and duration of use, preferred routes of intubation, limitation of sedation, protocolized weaning, optimal use of noninvasive mask ventilation, patient positioning, ventilator circuit management, transfusion practices, nutritional support issues, stress ulcer prophylaxis, and glycemic control. Local programs encompassing these interventions should be applied at a multidisciplinary level, involve all caregivers, and include local surveillance programs for antibiotic-resistant bacteria. The importance of implementing preventive strategies is amplified by the anticipated limited availability of new antimicrobial drug classes for the foreseeable future. Effective implementation of these preventive principles can result in significant cost savings for society and reduce hospital mortality and morbidity for individual patients.