Native valve infective endocarditis (NVE) is a global phenomenon, defined by infection of a native heart valve and involving the endocardial surface. The causes and epidemiology of the disease have evolved in recent decades, with a doubling of the average patient age. A higher incidence was observed in patients with implanted cardiac devices that can result in right-sided infection of the tricuspid valve. The microbiology of the disease has also changed. Previously, staphylococci, which are most often associated with health-care contact and invasive procedures, were the most common cause of the disease. This has now been superseded by streptococci. While innovative diagnostic and therapeutic strategies have emerged, mortality rates have not improved and remain at 30%, which is higher than that for many cancer diagnoses. The lack of randomized trials and logistical constraints impede clinical management, and long-standing controversies such as the use of antibiotic prophylaxis persist. This state of the art review addresses clinical practice, controversies, and strategies to combat this potentially devastating disease. A multidisciplinary team will be established to provide care for patients with presumptive NVE. The composition of the team will include specialists in cardiology, cardiovascular surgery, and infectious disease. The prompt administration of combination antimicrobial therapy is essential for effective NVE treatment. Additionally, a meticulous evaluation of each patient is necessary in order to identify any indications for immediate valve surgery. With the intention of promoting a more comprehensive understanding of the procedural management of native infective endocarditis and to furnish clinicians with a reference, the current evidence for the utilization of distinct strategies for the diagnosis and treatment of NVE are presented.