Successful treatment of patients with nosocomial pneumonia depends primarily on providing adequate initial antibiotic treatment in a timely manner, because an inappropriate course is closely associated with increased mortality. Gram-negative bacteria are commonly responsible for nosocomial pneumonia, and the increasing prevalence of drug resistance among these bacteria complicates decision making with regard to treatment with antibiotics. Infections due to Pseudomonas aeruginosa are particularly problematic because of their intrinsic resistance to multiple classes of antibiotics and their ability to acquire adaptive resistance during a therapeutic course. Numerous strategies, including the use of combination therapy followed by de-escalation of antibiotics, have shown promise in the treatment of these serious infections. However, future success in treating nosocomial infections depends on the appropriate and responsible use of antibiotics in the intensive care unit, to ensure that the antibiotics available today maintain their effectiveness in the future.