Pneumonia in the intensive care unit (ICU) has been associated with highly virulent pathogens that often exhibit resistance to multiple antibiotics and mortality rates of 30-70%. Pseudomonas aeruginosa and Enterobacteriaceae are the leading pathogens, followed by Staphylococcus aureus and polymicrobial etiologies. Recent clinical studies using monotherapy for nosocomial pneumonias resulted in low eradication rates for P. aeruginosa and staphylococci. An additional problem of these studies was the development of resistance by P. aeruginosa during the antibiotic treatment; also the selection of highly resistant strains like Xanthomonas maltophilia and Acinetobacter species was a major concern. However, several prospective studies comparing monotherapy versus combination therapy in nosocomial pneumonia of ICU patients have shown that a response rate of 60% is achievable, which is comparable to historic rates for combination therapy regimens. Only infections induced by P. aeruginosa, S. aureus, or other highly resistant pathogens (Acinetobacter, X. maltophilia, etc.) should be treated with well-defined antibiotic combinations.