In view of the mortality associated with Pseudomonas aeruginosa (PSA) ventilator-associated pneumonia (VAP) and the frequency of inadequate initial empiric therapy, recent findings underscore the need for a different management paradigm with effective anti-pseudomonal vaccines for prophylaxis of patients at risk. The association of virulence factors is a variable that splits PSA in two phenotypes, with the possibility of adjunctive immunomodulatory therapy for management of virulent strains. We comment on recent advances in and the state of the art of PSA-VAP management and discuss a new paradigm for tailored and optimal management.