The first glycopeptide antibiotic was vancomycin, isolated from the soil in the 1950s; since then, the class has expanded to include teicoplanin and the new semisynthetic glycopeptides dalbavancin, oritavancin and telavancin. They are bactericidal, active against most Gram-positive organisms, and in a concentration-dependent manner, inhibit cell wall synthesis. Resistance to vancomycin has emerged, especially among enterococci and Staphylococcus aureus through a variety of mechanisms. This emerging resistance to vancomycin makes proper dosing and monitoring of the area under the curve/MIC critically important. The chief adverse effect of vancomycin is nephrotoxicity, which is also intricately related to its dose. The efficacy of the semisynthetic glycopeptides has been demonstrated in skin and soft-tissue infections, but remains to be seen in serious methicillin-resistant Staphylococcus aureus infections.