The development of resistance in the major pathogenic Gram-positive genera Staphylococcus and Streptococccus has led to the need for new agents that are able to overcome existing resistance mechanisms or that have novel mechanisms of action. There is currently a dearth of new agents that are active against resistant bacterial species. Agents that have recently been approved for clinical use include linezolid, the first oxazolidinone in clinical use, daptomycin, the first lipopeptide in clinical use, and telithromycin, a ketolide that is derived from clarithromycin. Agents currently in clinical development include tigecycline, a broad-spectrum intravenous tetracycline, ceftobiprole, a broad-spectrum cephalosporin that has activity against methicillin-resistant staphylococci, DX-619 and WCK-771, which are potent quinolones that have activity against quinolone-resistant staphylococci, oritavancin and dalbavancin, both of which are new glycopeptides, and iclaprim, which is a diaminopyrimidine. Additional agents that are in preclinical development against Gram-positive pathogens include quinoline-naphthyridine agents, which target novel DNA gyrase sites, other novel quinolones that have high potency, peptide deformylase inhibitors, and new lincosamide, oxazolidinone, lipopeptide and cephalosporin derivatives. Misuse of potent new agents will, however, result in the inevitable development of resistance to these agents; responsible use of potent new agents is required to prevent continuation of this vicious cycle.