Resistance to antibiotics among gram-positive bacteria, especially enterococci and staphylococci, has led to the need to develop new antibiotics. Vancomycin, a glycopeptide antibiotic, has been used for over 3 decades to treat serious methicillin-resistant Staphylococcus aureus infections. The increased frequency of multidrug-resistant bacteria, especially vancomycin-resistant strains, has focused interest on three new lipoglycopeptides for the treatment of infections caused by gram-positive bacteria: oritavancin, dalbavancin, and telavancin. Although oritavancin and dalbavancin are still in development, telavancin received approval from the United States Food and Drug Administration in September 2009 for treatment of complicated skin and skin structure infections. Structurally different from vancomycin and teicoplanin, all three lipoglycopeptides have greater potency and less potential for development of resistant organisms. Of particular importance is the activity of oritavancin, dalbavancin, and telavancin against vancomycin-resistant organisms. In addition, the pharmacokinetic properties of these new antimicrobials substantially differ from those of vancomycin. Both oritavancin and dalbavancin have long terminal half-lives, which may allow for infrequent dosing. In addition, oritavancin is primarily cleared through hepatic pathways, which makes it potentially useful in patients with renal compromise. In animal models, these new lipoglycopeptides were effective in treating serious gram-positive infections, including complicated skin and skin structure infections, endocarditis, bacteremia, and pneumonia; in clinical studies, however, efficacy was shown only in complicated skin and skin structure infections for all three agents. According to preliminary data, the adverse-effect profile of these lipoglycopeptides is generally similar to that of drugs currently used to treat severe gram-positive infections. However, further evaluation and monitoring is necessary as more patients are exposed to these agents. As antimicrobial resistance continues to increase worldwide, the lipoglycopeptides may provide clinicians with a useful antimicrobial in the continued fight against multidrug-resistant gram-positive bacteria.