This review summarizes the rationale for using or not using combinations of antibiotics to treat ventilator-associated pneumonia (VAP). Patients suffering from VAP require empirical antibiotic treatment before the identification of an etiologic agent. Most treatment failures are related to inappropriate initial antibiotic treatment with insufficient coverage of multidrug-resistant (MDR) pathogens. Guidelines require initial (empirical) treatment of VAP with a combination of antibiotics. However, this contributes to overexposure to antibiotics and further emergence of MDR microorganisms. We review the rationale for using combinations of antibiotics to cover MDR gram-negatives. However, clinical data supporting this strategy are limited. In fact, systematic combination therapy may have contributed to the overuse of antibiotics and to the emergence of MDR microorganisms. Nevertheless, combination therapy is our best strategy to treat severe infections due to suspected MDR microorganisms. Optimally, therapeutic strategies should be sufficiently broad to cover relevant pathogens while minimizing the risk for emergence of antimicrobial resistance.