Enteroccocal infective endocarditis is a major challenge to clinicians. There are an increasing number of reports of nosocomial acquisition and multidrug-resistant strains complicating management. The therapy of choice for enterococcal endocarditis remains ampicillin and gentamicin; however, high levels of aminoglycoside resistance, vancomycin-resistance, and toxicity of gentamicin with prolonged therapy have necessitated the use of other options in some patients. When the combination of cell wall drug and aminoglycoside cannot be used, the optimal regimen is not well established, due to limited information from clinical trials. There is thus an urgent need to better understand pathogenesis, resistance mechanisms, and optimal management strategies. Clinicians need to explore both antimicrobial and nonantimicrobial strategies for management, including evaluation of those at risk, early diagnosis, appropriate combination, and infection prevention.