Ventilator-associated pneumonia (VAP) is a significant clinical infection affecting up to one-third of patients requiring mechanical ventilation, and is associated with significant attributable morbidity and mortality. Clinicians should have a heightened clinical suspicion for VAP with diagnostic goals focusing on accuracy; gathering of lower respiratory tract culture; and appropriate and timely initial antibiotic therapy. Early and adequate antibiotic therapy is important to optimize the management of patients with VAP. The incidence and etiologic patterns of the major pathogens causing VAP must be taken into account when making empiric antibiotic therapy choices. Subsequent de-escalation and prescription of an appropriate duration of therapy guided by clinical response and culture results may lead to decreased morbidity and future antibiotic resistance.