Surveillance data demonstrate that the majority of gram-positive bacterial isolates obtained in the intensive care unit (ICU) setting are staphylococci and enterococci. Staphylococci, mainly Staphylococcus aureus and coagulase-negative staphylococci, compose the majority of clinical isolates. Data from 25 North American ICUs reported methicillin-resistant Saureus (MRSA) in more than 50% of the Saureus organisms isolated mainly from a respiratory source. In addition to MRSA, Saureus with reduced susceptibility to vancomycin has been reported. Enterococci are typically considered opportunistic pathogens, infecting immunocompromised hosts. Resistance of enterococci to vancomycin, along with the newer gram-positive antimicrobials, is an increasing problem. Investigators have demonstrated that nearly 30% of enterococci isolated in the ICU are resistant to vancomycin. The high level of resistance and limited therapeutic options make treating resistant gram-positive organisms such as MRSA and vancomycin-resistant enterococci particularly problematic. While vancomycin has long been considered the gold standard for the treatment of resistant gram-positive infections, newer agents (eg, quinupristin-dalfopristin, linezolid, and daptomycin) offer therapeutic alternatives.