Infective endocarditis (IE) represented over the last year a growing medical and surgical concern.The changes in etiology and demographic of the disease, which now includes also a large proportion of iatrogenic conditions, has prompted new studies and updates in the guideline for IE treatment. The increasing use of intravascular and intracardiac devices has introduced new challenges in terms of both antibiotic resistance and surgical treatment of prosthetic endocarditis. Also, patients with complex congenital heart diseases, intravenous drug abusers and patients with chronic renal failure under hemodialysis have been added to the list of high-risk subjects for IE. Important aspects concerning the establishment of the endocarditis team, the clinical management, the optimal medical therapy and the indication and timing for surgery are arguments of debate and controversy across the literature. In particular, the most adequate strategy to be adopted in the context of concomitant neurological complication remains greatly debated.Despite attempts to standardize the practice in IE, the lack of powered randomized clinical evidence prevented the achievement of a univocal consensus in several aspects of the management of IE. This situation reflects in some differences in the recommendation promoted by the European Society of Cardiology and American Heart Association/American College of Cardiology. In this review, we will compare the European Society of Cardiology and the American Heart Association guidelines and discuss important aspects related to clinical management and indications of for treatment.