The Gram-positive species Enterococcus faecium has long been thought of as a harmless commensal of the mammalian GI tract. In the last two decades, however, E. faecium has become an important cause of nosocomial bacteremias. These infections are often difficult to treat owing to the resistance of E. faecium to a large number of antibiotics. In this article, we review the recent transition of E. faecium from commensal to nosocomial pathogen. We focus on population biology-based studies, which suggest that several clonal populations of E. faecium are mostly responsible for causing infections. We also discuss the role of the accessory genome of E. faecium in contributing to the infectious phenotype and examine the role that surface proteins of E. faecium may have in colonization and infection.