Despite the availability of new and potent antibiotics, modern echocardiography, and advanced surgical techniques, infective endocarditis (IE) is still associated with high morbidity and mortality rates. Use of synergistic antibiotic combinations is an appealing way to optimize therapy for IE. This review focuses on evidence-based recommendations for combination antimicrobial therapy for IE due to the most common etiologic pathogens. Few proven synergistic approaches for the treatment of IE have been globally demonstrated via in vitro models, experimental IE models, and human clinical trials, except for IE due to enterococci. Novel approaches, such as short-course aminoglycoside therapy and double-beta-lactam combination therapy, appear to be promising for treatment of enterococcal IE. Short-course combination therapy involving agents with activity against the cell wall (CWAs) and aminoglycosides is highly effective for IE caused by viridans group streptococci. Although synergistic combination therapy with CWAs-aminoglycosides remains widely used by clinicians for Staphylococcus aureus IE, few definitive human data exist that demonstrate the clinical benefit of such an approach.