The treatment of severe enterococcal infections based on the currently available antibacterial agents is difficult. The help of the microbiology laboratory for determining MICs, MBCs, and most effective synergistic combinations is crucial. There is a need for good prospective multicenter clinical trials to improve the prognosis of such infections by defining therapeutic strategies better. Such a requirement is highly suitable for the treatment of infections caused by enterococci exhibiting acquired resistance mechanisms to the available agents. The current clinical development of new compounds looks promising in these persistently life-threatening infections mostly occurring in deficient hosts.