Infective endocarditis (IE) occurs at a rate of approximately 0.9-6.2 per 100,000 people per year and is associated with a high morbidity and mortality despite advancements in antibiotic and surgical treatments. The general approach to the treatment of IE is initial clinical stabilization, early acquisition of blood cultures, and definitive medical and/or surgical treatment. Surgical consultation should be obtained early when indicated in order to determine the best treatment approach for each individual patient. Surgery is indicated in most cases of prosthetic valve endocarditis, Staphylococcus aureus endocarditis, fungal endocarditis, and endocarditis associated with large vegetations (≥10 mm). Initial antibiotic therapy for IE should be targeted to the culprit microorganism; however, in some cases, empiric therapy must be initiated prior to definitive culture diagnosis. Empiric antibiotics should be targeted toward the most likely pathogens, including staphylococci, streptococci, and enterococci species. Here we discuss the recommended antibiotic regimens for the most common causes of IE as indicated by the American Heart Association and European Society of Cardiology. In 2008, the ACC/AHA published guideline updates on the treatment of valvular heart disease, which included a focused update on endocarditis prophylaxis. According to the most recent guidelines, the number of patients who require antibiotic prophylaxis has decreased substantially. Treatment of IE should be targeted toward the causative microorganism and must be based on the type and location of valve involved (native, prosthetic, left or right sided), the clinical status of the patient, and the likelihood for clinical success. This requires a collaborative effort from multiple medical specialties including infectious disease specialists, cardiologists, and cardiothoracic surgeons.