Daptomycin is a Food and Drug Administration-approved alternative to vancomycin for the treatment of serious methicillin-resistant Staphylococcus aureus infections in adults. Treatment failure with daptomycin is increasingly reported in adults, but data in children are limited. We report an adolescent patient with severe burn injuries who had persistent methicillin-resistant Staphylococcus aureus bacteremia and rapidly developed nonsusceptibility to daptomycin. We review the relevant literature.