The current incidence of infective endocarditis (IE) is estimated as 7 cases per 100,000 population per year and continues to increase. The prognosis is significantly influenced by proper diagnosis and adequate therapy. In cases with unconfirmed IE, transesophageal echocardiography is the imaging technique of choice. Culture-negative endocarditis requires either termination of antimicrobial treatment initiated without mircobiological test results and reevaluation of blood samples or serological/molecular biological techniques to identify the causative organism. Antimicrobial therapy should be established only after quantitative sensitivity tests of antibiotics (minimal inhibitory concentrations, MIC) and guided by drug monitoring. In the first 3 weeks after primary manifestation, an index embolism is frequently followed by recurrencies. If vegetations can still be demonstrated by echocardiography after an embolic event, a surgical intervention should seriously be considered. Cerebral embolic events are no contraindication for cardiac surgery, as long as a cerebral bleeding has been excluded by cranial computed tomography immediately preoperatively and the operation is performed before a significant disturbance of the blood-brain barrier (<72 hours) has manifested. A significant prognostic improvement has also been demonstrated for patients with early surgical intervention suffering from myocardial failure due to acute valve incompetence, acute renal failure, mitral kissing vegetations in primary aortic valve IE, and in patients with sepsis persisting for more than 48 hours despite adequate antimicrobial therapy.