Ventilator-associated pneumonia (VAP), which develops in patients receiving mechanical ventilation, is the most common nosocomial infection in patients with acute respiratory failure. The major mechanism of lower respiratory tract colonization is aspiration of bacteria-colonized secretions from the oropharynx into the lower airways. The hydrostatic pressure of the secretions that collect in the subglottic space, which is the area above the endotracheal tube (ETT) cuff, or aerosolization of bacteria from the secretions collected within the respiratory tubing may facilitate the leakage into the lower airways. Ideally, the elimination of the mechanisms responsible for aspiration would decrease the incidence of VAP. Several preventive measures have been tested in clinical trials with little success.Here we present the results of our efforts to develop novel approaches for the prevention of VAP. Specifically, we found that keeping ventilated patients in a lateral position, which eliminates gravitational forces, is feasible and possibly advantageous. Additionally, several novel medical devices have been recently developed to prevent bacterial biofilm formation from the ETT and breathing tubing. These devices include coated ETTs, mucus shavers and mucus slurpers. Prevention of ETT bacterial colonization showed decreased bacterial colonization of the respiratory circuit and of the lower respiratory tract in laboratory studies and clinical trials. Future large studies should be designed to test the hypothesis that VAP can be prevented with these novel strategies. While there is a current focus on the use of respiratory devices to prevent biofilm formation and microaspiration, it is important to remember that lower respiratory tract colonization is multifactorial. Prevention of VAP cannot be achieved solely by eliminating bacterial biofilm on respiratory devices, and more comprehensive care of the intubated patient needs to be implemented.