Daptomycin, a new cyclic lipopeptide, was recently approved for the treatment of infections by gram-positive organisms, including infections with methicillin-resistant Staphylococcus aureus (MRSA). A patient infected with infected with MRSA developed resistance to daptomycin after prolonged exposure, which resulted in clinical failure. Clinicians should be aware of the possibility of daptomycin resistance and should consider routine testing for daptomycin susceptibility.