Ventilator-associate pneumonia (VAP) is the most common nosocomial infection in patients in intensive care units (ICU). Because of its association with unwanted clinical outcomes, preventive measures have been studied intensively in the past 25 years. Unfortunately, a large amount of clinical trials yielded disappointingly few clear-cut answers. Furthermore, because of the difficulties in reliably diagnosing VAP, we should be very reluctant in embracing measures that have been associated with VAP reductions in small-sized studies, but with no benefits on patient outcome documented in sufficiently powered well-designed trials. Only topical antimicrobial prophylaxis (either alone in the oropharynx or in combination with intestinal decontamination) has been demonstrated to improve patient outcome resulting from prevention of VAP. However, this was demonstrated in not-so-average circumstances-in ICUs with extremely low levels of antibiotic resistance. Despite the obvious challenges with using antibiotics as preventive measures, careful evaluation of these strategies in settings with higher drug-resistance levels is now justified, and future studies should be designed to demonstrate outcome benefits rather than reductions in VAP rates.