Among various risk factors for death among critically ill patients with serious infection, inappropriate antimicrobial therapy is an important factor that clinicians can modify directly. The presence of multidrug-resistant bacteria is the primary reason that patients with ventilator-associated pneumonia receive inappropriate antimicrobial therapy. Empirical antimicrobial therapy for ventilator-associated pneumonia should be initiated promptly and should have a broad spectrum that covers all potential antimicrobial-resistant pathogens. Delaying the start of therapy or modifying an inappropriate antimicrobial regimen does not improve outcome, probably because the change comes too late to redirect the course of illness. Timely empirical therapy with highly effective agents that are rapidly bactericidal could minimize the emergence of resistance. Broad-spectrum therapy should be streamlined (i.e., de-escalated), as appropriate, on the basis of microbiological data and clinical response. Switching to narrower-spectrum therapy that is directed by culture results may minimize the emergence of resistance. For some patients, clinical response will allow a shortening of the duration of antimicrobial therapy.