As prosthetic cardiovascular devices become more common, the risk of complicating infections increases. The confluence of high-risk procedures, prosthetic material and antibiotic-resistant bacteria has made the management of these cardiovascular infections a challenge. A limited number of new antimicrobial agents have been introduced with activity against the resistant gram-positive organisms that are responsible for such problematic cardiovascular infections. Among these are the new agents quinupristin/dalfopristin and linezolid. In addition, several new therapeutic agents (e.g. daptomycin, lysostaphin and a Staphylococcus aureus vaccine) are in varying stages of clinical trials. Other strategies, such as the use of synergistic antibiotic combinations, the prophylactic eradication of bacterial colonization and the exploration of agents specifically targeting bacterial biofilms, are potentially valuable methods that are currently under investigation.