Today, enterococci (mainly Enterococcus faecalis) are one of the main causes of infective endocarditis in the world, generally affecting an elderly and fragile population, with a high mortality rate. enterococci are intrinsically resistant to many commonly used antimicrobial agents. All enterococci exhibit decreased susceptibility to penicillin and ampicillin, as well as high-level resistance to most cephalosporins and all semi-synthetic penicillins, as the result of expression of low-affinity penicillin-binding proteins, that precludes an unacceptable number of therapeutic failures with monotherapy with these drugs. For years, the synergistic combination of penicillins and aminoglycosides was the cornerstone of treatment, but the emergence of strains with high resistance to aminoglycosides led to the search for new alternatives, such as dual beta-lactam therapy. The development of multi-drug resistant strains of Enterococcus faecium is a matter of considerable concern due to its probable spread to E. faecalis and have forced the search of new alternatives with the combination of daptomycin, fosfomycin or tigecycline. Some of them have scarce clinical experience and others are still under investigation and will be analyzed in this review. In addition, the need for prolonged treatment (6-8 weeks) to avoid relapses has led to the consideration of viable options such as outpatient parenteral therapies or long-acting administrations with the new lipoglycopeptides (dalbavancin or oritavancin), and sequential oral treatments, which will also be discussed.