In the last 5 years, clinical isolates of gram-positive bacteria with intrinsic or acquired resistance to glycopeptide antibiotics have been encountered increasingly. In many of these isolates, resistance arises from an alteration of the antibiotic target site, with the terminal D-alanyl-D-alanine moiety of peptidoglycan precursors being replaced by groups that do not bind glycopeptides. Although the criteria for defining resistance have been revised frequently, the reliable detection of low-level glycopeptide resistance remains problematic and is influenced by the method chosen. Glycopeptide-resistant enterococci have emerged as a particular problem in hospitals, where in addition to sporadic cases, clusters of infections with evidence of interpatient spread have occurred. Studies using molecular typing methods have implicated colonization of patients, staff carriage, and environmental contamination in the dissemination of these bacteria. Choice of antimicrobial therapy for infections caused by glycopeptide-resistant bacteria may be complicated by resistance to other antibiotics. Severe therapeutic difficulties are being encountered among patients infected with enterococci, with some infections being untreatable with currently available antibiotics.