Prosthetic valve endocarditis (PVE) is an important cause of the morbidity and mortality associated with heart valve replacement surgery. Once established, it carries a mortality rate that may be as high as 70%. The only treatment for established PVE is rigorous intravenous antimicrobial therapy, although this has extremely limited success. The majority of cases require surgical removal and replacement of the infected prosthesis. At present, the only means of preventing PVE are scrupulous asepsis and prophylactic perioperative antibiotic therapy. If another strategy could be developed that is effective and safe, the incidence of this disastrous complication of valve replacement would be reduced. Such strategies have been extensively investigated from a variety of different perspectives for several years. The understanding of biofilms appears to be pivotal to the development of a successful approach. The historic background to the prevention of PVE, and the current state of research into this area are discussed.