Among Gram-positive pathogens, Staphylococcus aureus is the leading cause of death from nosocomial pneumonia. The bacterium developed progressive resistance to beta-lactams, and methicillin-resistant strains emerged in the 1980s. In consequence, vancomycin has become the drug of choice for treatment of this infection over the last decade, based on susceptibility tests and the serum antimicrobial levels recorded. However, half of the patients treated with vancomycin have died. In contrast, in patients receiving beta-lactams for pneumonia caused by methicillin-sensitive S. aureus, survival is the rule. These observations, together with the emergence of isolates with reduced susceptibility to glycopeptides, raised concern about the use of vancomycin as standard therapy for pneumonia caused by Gram-positive cocci. Maintaining tissue levels above minimal inhibitory concentration is vital to successful clinical outcome. Optimizing treatment focusing on this goal and new antimicrobials provide new opportunities to improve survival. (Crit Care Med 2001; 29[Suppl.]:N82-N86)