Infections related to cardiac surgery increase morbidity and mortality, and increase cost and use of health resources. With the widespread use of synthetic materials, whether in prosthetic valves or vascular conduits, bacterial infection and, more rarely, fungal complications can be devastating, requiring prolonged antimicrobial therapy and, at times, re-operations with high morbidity and mortality rates. With the US population aging and living longer, cardiac surgery is applied to an older population with significant comorbidities, making the threat from infectious complications significant. The dwindling armamentarium of existing antimicrobial agents, a limited pharmaceutical pipeline of future therapies, and the emergence of antimicrobial-resistant bacteria have increased the challenge of treating cardiothoracic infections. Thus, there is critical need for addressing the existing and emerging issues in this area to develop new safe and effective strategies to address the clinical challenges facing cardiothoracic surgeons. As a result of this need, the National Heart, Lung, and Blood Institute and the National Institute of Allergy and Infectious Diseases convened a Working Group on April 4 and 5, 2002, in Bethesda, Md, which explored both basic science and clinical research opportunities in the prevention and treatment of major infections after cardiac surgery. Because of its importance as the most common pathogen in this setting, the focus of discussions was on the prevention and treatment of Staphylococcus aureus infections. This report summarizes the 5 main areas that the Working Group targeted (epidemiology of infections, molecular mechanisms of infections and complications, current pharmacotherapy, new frontiers, and clinical trial design) and highlights the recommendations that were set forth by the Working Group.