The unmet medical need of emerging resistance among Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, has driven industry towards the identification and development of novel anti-Gram-positive agents. Among the newer agents are improved quinolones, a lipopeptide, an oxazolidinone and novel glycopeptides. Scientific distinctions between these drugs, which impact on the placement, usage and, ultimately, the pharmacoeconomics of several of these new agents, may lead to further consideration despite poor initial observations of minimal improvement. Key differences in the characteristics of these drugs (i.e., spectrum, activity, resistance emergence, efficacy, target, safety) provide a basis for an emerging pharmacoeconomic-based distinction between these newer anti-Gram-positive agents.