We review the history of vancomycin-resistant enterococci (VRE) and propose a causal model illustrating the roles of exposure to VRE reservoirs, patient characteristics, antimicrobial exposure, and prevalence of VRE in the progression from potential VRE reservoirs to active disease in hospitalized patients. Differences in VRE colonization and VRE infection are discussed with respect to hospital surveillance methodology and implications for interventions. We further document clonal transmission of VRE in a large, urban, teaching hospital and demonstrate VRE susceptibility to a wide array of antimicrobial agents. This model can guide the identification of mutable factors that are focal points for intervention. © 2003 The Hospital Infection Society.