Ventilator-associated pneumonia (VAP) is the most common hospital-acquired infection in the intensive care unit (ICU), accounting for relevant morbidity and mortality among critically ill patients, especially when caused by multidrug resistant (MDR) organisms. The rising problem of MDR etiologies, which has led to a reduction in treatment options, have increased clinician’s attention to the employment of effective prevention strategies. In this narrative review we summarized the evidence resulting from 27 original articles that were identified through a systematic database search of the last 15 years, focusing on several pathogenesis-targeted strategies which could help preventing MDR-VAP. Oral hygiene with Chlorhexidine (CHX), CHX body washing, selective oral decontamination (SOD) and/or digestive decontamination (SDD), multiple decontamination regimens, probiotics, subglottic secretions drainage (SSD), special cuff material and shape, silver-coated endotracheal tubes (ETTs), universal use of gloves and contact isolation, alcohol-based hand gel, vaporized hydrogen peroxide, and bundles of care have been addressed. The most convincing evidence came from interventions directly addressed against the key factors of MDR-VAP pathogenesis, especially when they are jointly implemented into bundles. Further research, however, is warranted to identify the most effective combination.