Two novel lipoglycopeptides, dalbavancin and telavancin, and relevant comparative agents were tested for in vitro activity against clinical isolates of staphylococci and streptococci collected in the cross-Canada surveillance study, CANWARD, in 2007–2009. The rank order of potency (based on MIC 90 [μg/mL], i.e., the concentration of antimicrobial agent required to inhibit the growth of 90% of isolates tested) of glycopeptides against both Staphylococcus aureus and Staphylococcus epidermidis was dalbavancin (0.06 μg/mL) >telavancin (0.5 μg/mL) > vancomycin (1–2 μg/mL); concurrent susceptibility or resistance to oxacillin in staphylococci did not affect potency of glycopeptides. Dalbavancin and telavancin also demonstrated potent activity against Streptococcus pneumoniae, including penicillin-resistant isolates (MIC 90 , ≤0.03 μg/mL; ≤0.06 μg/mL), and Streptococcus pyogenes (≤0.03 μg/mL; 0.06 μg/mL). Based on their robust in vitro activities, dalbavancin and telavancin have the potential to treat Gram-positive infections caused by methicillin-resistant Staphylococcus aureus and penicillin-resistant Streptococcus pneumoniae.