The Gram-positive cocci have clearly re-emerged as important pathogens world-wide in the past two decades. Staphylococci, including the coagulase-negative staphylococci and Staphylococcus aureus, and the enterococci account for approximately one-third of all blood stream infections and as much as 50% of nosocomial blood stream infections. Although Streptococcus pneumoniae is often considered a community-acquired pathogen, it is also an important cause of nosocomial infection. The hallmark of these Gram-positive pathogens is increasing resistance to available antimicrobial agents. Of particular note is resistance to glycopeptides (vancomycin and teicoplanin), aminoglycosides (high-level), and penicillins among the enterococci (especially E. faecium), resistance to penicillinase-resistant penicillins (oxacillin and methicillin) and fluoroquinolones (ciprofloxacin and ofloxacin) among staphylococci, and resistance to penicillin, other beta-lactams and macrolides among the pneumococci. The recent detection of decreased susceptibility to vancomycin among S. aureus is also quite ominous. In many instances the ability of the clinical laboratory to accurately characterize these resistant isolates is suboptimal, further compounding the problem. Increased understanding of resistance mechanisms and correlations of resistance genes with the phenotypic expression of resistance has allowed for modifications and improvements of reference susceptibility tests and interpretive breakpoints. New compounds for effective therapy of infection with multi-resistant Gram-positive species are clearly needed. To this end, the streptogramin combination, quinupristin/dalfopristin, has demonstrated significant activity against oxacillin-resistant staphylococci, penicillin-resistant streptococci, and vancomycin-resistant E. faecium. Other candidate drugs including Gram-positive active fluoroquinolones (clinafloxacin, grepafloxacin, moxifloxacin, gatifloxacin, and trovafloxacin) and novel compounds such as the everninomicin derivatives (SCH27899), ketolides, and oxazolidinones (linezolid) have been shown to be active against these organisms and are under rapid clinical development.