Infective endocarditis is a life-threatening disease caused by a focus of infection within the heart. For clinicians and scientists, it has been a moving target that has an evolving microbiology and a changing patient demographic. In the absence of an extensive evidence base to guide clinical practice, controversies abound. Here, we review three main areas of uncertainty: first, in prevention of infective endocarditis, including the role of antibiotic prophylaxis and strategies to reduce health care-associated bacteraemia; second, in diagnosis, specifically the use of multimodality imaging; third, we discuss the optimal timing of surgical intervention and the challenges posed by increasing rates of cardiac device infection.