Vancomycin is active against most Gram-positive bacteria. The genera Leuconostoc, Lactobacillus, Pediococcus and Erysipelothrix are normally resistant to vancomycin but do not represent a major problem because the incidence of infections caused by these organisms is low and they are usually susceptible to other antimicrobial agents. More disturbing, however, is the emergence of vancomycin resistance in clinical enterococcal and staphylococcal isolates. Acquisition of new genes is responsible for vancomycin resistance in isolates of Enterococcus faecalis and Enterococcus faecium. Whereas low-level vancomycin resistance appears to be a normal or inherent characteristic of Enterococcus gallinarum and Enterococcus casseliflavus. To date, vancomycin resistance has not been reported in clinical isolates of Streptococcus spp. or Staphylococcus aureus. However, stepwise decreases in vancomycin susceptibility have been observed in coagulase-negative staphylococci, particularly Staphylococcus haemolyticus. Because coagulase-negative staphylococci and enterococci are now the second and third most common organisms causing hospitalacquired bloodstream infection in the USA, respectively, and because resistance to vancomycin in these organisms is usually accompanied by multiple resistance to antimicrobial agents, vancomycin-resistant enterococci and staphylococci represent a major problem for the physician. Efforts to avoid their emergence by appropriate antibiotic use and to stop their dissemination by adherence to infection control practices are needed as few therapeutic alternatives are currently available.