Ventilator-associated pneumonia (VAP) is a pervasive and expensive nosocomial infection that is largely related to instrumentation of the airway with an endotracheal tube (ETT), followed by microaspiration of contaminated secretions. VAP prevention will probably be most effective via a multifaceted approach, which includes meticulous attention to basic infection-control methods during patient care, proper patient positioning, oral hygiene, and removal of the ETT as soon as indicated. Modification of the ETT to reduce microaspiration and/or biofilm formation may also play an important role in VAP prevention. However, despite numerous studies of various such interventions, there is insufficient evidence upon which to base strong recommendations, and important safety concerns remain regarding the use of some devices. Most importantly, cost-effectiveness data are lacking for modified ETTs designed to prevent VAP. It is critical that future studies of ETTs designed to prevent VAP be adequately powered to demonstrate efficacy on important patient outcomes and safety, in addition to cost-effectiveness.