Previously, Staphylococcus epidermidis and other coagulase-negative staphylococci isolated from the blood of hospitalized patients were often considered contaminants. Now, coagulase-negative staphylococci are among the leading causes of nosocomial blood infections. Multidrug resistance could predict a true nosocomial infection rather than a blood culture contaminant. Recent studies indicated the emergence of resistance to the quinolones, particularly to ciprofloxacin. Tolerance and occasional resistance to vancomycin have been reported recently. In addition, several reports indicated that vancomycin and other glycopeptide antibiotics lose their effectiveness against S. epidermidis organisms embedded in the biofilm environment on the surface of medical devices. Alternative agents have been proposed in the prevention and treatment of device-related and glycopeptide-tolerant S. epidermidis infections. These agents include minocycline, rifampin, and, more recently, quinupristin/dalfopristin and the oxazolidinones.