Daptomycin, a cyclic lipopeptide antibiotic, has been approved for use in complicated gram-positive skin and soft tissue infections, Staphylococcus aureus bacteremia, and right-sided endocarditis. Because of its unique mechanism of action, daptomycin is rapidly bactericidal without inducing cell lysis, a feature which might make it an attractive agent for use in gram-positive meningitis. Daptomycin has been used successfully in rabbit and rat meningitis models. Despite this experience, daptomycin has not been evaluated in humans for meningeal infections because it is highly protein bound (∼92%) and has relatively low cerebrospinal fluid penetration. We report our experience using a daptomycin-based regimen to manage a methicillin-resistant S. aureus meningitis case and discuss the prospects for using daptomycin in staphylococcal meningitis.