Telavancin (TLV) is a novel, rapidly bactericidal lipoglycopeptide with potent antibacterial activity against Gram-positive bacteria including methicillin-resistant S. aureus.  TLV has completed two Phase 3 clinical trials for the treatment of complicated skin and skin structure infections and is currently being evaluated for the treatment of hospital-acquired pneumonia.  The design of TLV included incorporation of a highly specific lipophilic, decylaminoethyl-sidechain appended to the vancosamine sugar of vancomycin.  As a consequence of this modification, TLV possesses two potentially interdependent mechanisms of action that account for its potent bactericidal activity and broad Gram‑positive spectrum of action.  A number of lines of investigation will be presented that support the conclusion that TLV is a potent, substrate-targeted inhibitor of peptidoglycan (PG) biosynthesis with many mechanistic features in common with marketed glycopeptide antibiotics.  TLV’s decylaminoethyl substituent confers enhanced membrane targeting and preferential inhibition of the transglycosylation step of peptidoglycan biosynthesis relative to vancomycin.  In addition to the effects of TLV on PG biosynthesis, TLV interacts directly with the bacterial membrane and lipid II to disrupt membrane barrier function, resulting in time- and concentration-dependent loss of membrane potential and increased membrane permeability.  The combined impact of inhibition of PG biosynthesis and effects on the bacterial cell membrane mediate the antibacterial activity of TLV and contribute to its rapid bactericidal effects.  As a result of this dual, multivalent mechanism of action, TLV exhibits superior in vitro antibacterial properties compared to vancomycin, including enhanced potency and spectrum, and rapid bactericidal activity against Gram‑positive bacteria at therapeutically relevant concentrations.