Daptomycin is the only antibiotic with in vitro bactericidal activity against vancomycin-resistant Enterococcus (VRE) that is approved by the Food and Drug Administration (FDA). Data on the potential emergence of daptomycin nonsusceptibility among enterococci remain limited. We systematically reviewed the published literature for reports of isolates of enterococci that were daptomycin nonsusceptible and assessed the clinical significance and outcome of therapy. Based on susceptibility breakpoints approved by the Clinical Laboratory Standards Institute (CLSI), daptomycin has in vitro activity against >90% of enterococcal isolates. Less than 2% of enterococcal isolates were daptomycin nonsusceptible, with minimum inhibitory concentrations (MICs) >4 μg/mL. The prevalence of nonsusceptibility of VRE isolates to daptomycin may be overestimated due to the spread of clonally related isolates in health care settings. Clinicians should be aware of the possibility of the emergence of daptomycin nonsusceptibility and should closely monitor daptomycin MICs of enterococci isolated during treatment.