Multidrug-resistant Gram-positive infections remain a significant therapeutic problem, especially those due to Staphylococcus aureus. Antimicrobial choice is only one aspect of the management of these infections. New immunotherapies, exploitation of novel antibiotic targets, topical therapies and new drug delivery systems may have a future role in the management of S. aureus infection. At present, injectable antimicrobials are the main area of drug development and clinical interest. Since 1999, five anti-Gram-positive agents (moxifloxacin, quinupristin-dalfopristin, linezolid, daptomycin and tigecycline) have become available in the EU. At present, three other anti-Gram-positive agents are being considered by the European Medicines Agency (ceftobiprole, gemifloxacin and iclaprim), and a further four have completed phase III clinical trials (ceftaroline, dalbavancin, oritavancin and telavancin). The antibacterial spectra of these agents, their in vitro potencies, bactericidal activities and pharmacokinetics are well known. The safety profiles for those agents that have received regulatory approval and entered clinical practice are also firmly established. Most of the agents are pharmacodynamically promising and effective in clinical trials. As in the past, drug safety is likely to be a major determinant of which of the most recent drugs receive regulatory approval, and, in the long term, which agents will be successful in clinical practice.