A number of factors have been suspected of or identified as increasing the risk for pneumonia or colonization of the lower respiratory tract by Pseudomonas and/or Acinetobacter spp. in the intensive care unit (ICU), including advanced age, chronic lung disease, immunosuppression, surgery, use of antimicrobial agents, presence of such invasive devices as endotracheal and gastric tubes, and type of respiratory equipment. However, there is little doubt that of all these factors, extended ICU care because of severe underlying disease, prolonged respiratory therapy with mechanical ventilation, and prior antimicrobial therapy are the most important. Because the only factor amenable to prevention in this setting is antimicrobial therapy, avoiding unnecessary antibiotics should be a high priority in the management of such patients. Crude mortality rates of 30% to 75% have been reported for nosocomial pneumonia caused by Pseudomonas and/or Acinetobacter spp., with the highest rates reported in ventilator-dependent patients. It is therefore clear that the prognosis associated with this type of infection is considerably worse than that associated with infection caused by other gram-negative or gram-positive bacteria. Because bactericidal synergy against Pseudomonas and Acinetobacter spp. has been shown when carbenicillin and an aminoglycoside are combined, the use of an effective beta-lactam (piperacillin, ticarcillin, ceftazidime, or imipenem) and aminoglycoside combination remains the preferred therapeutic approach when possible. Future research efforts should also aim to improve our ability to diagnose and exclude infection in the ICU setting to avoid administering unnecessary antibiotics to patients without true pulmonary infection.