Infective endocarditis is an infection of cardiovascular structures which is typically caused by bacteria. Despite recent medical advances mortality ranges from 20 to 25%. Without treatment, IE is a lethal disease. The mortality rate depends on several clinical factors including the causative microorganism, the time of diagnosis, and the initiation of an adequate therapeutic regimen. The diagnosis is based on positive blood culture results with identical microorganisms and the demonstration of endocardial involvement. Negative blood cultures represent a diagnostic challenge which may increase the importance of diagnostic tools such as serology and PCR. An early and targeted initiation of an antibiotic therapy after microbiologic testing is crucial for therapeutic success. The immediate cooperation of Cardiologists, Microbiologists, Infectious Disease Specialists and Cardiac Surgeons is highly recommended to allow an adequate medical and surgical treatment in complex cases.Prophylaxis appears reasonable due to the inherent high mortality. The efficacy of an antibiotic prophylaxis is, nevertheless, not rigorously proven. Even if a high efficacy is assumed, the number needed to treat is extremely high due to the low individual risk. Thus, current guidelines recommend an antibiotic prophylaxis only in patients with a high risk for an adverse outcome.