Infective endocarditis (IE) continues to present a large burden to the health-care system. Staphylococcus aureus, the leading pathogen associated with the disease, has always proven difficult to treat. Increasing numbers of S. aureus isolates are demonstrating reduced susceptibility to vancomycin, and therapeutic options are limited. Daptomycin is frequently employed when vancomycin therapy proves unsuccessful or when vancomycin minimum inhibitory concentration (MIC) values rise above 1 mg/L. Currently, daptomycin is FDA-approved at a dose of 6 mg/kg/day for the treatment of S. aureus bacteremia and associated right-sided endocarditis. However, numerous in vitro and clinical studies suggest that daptomycin doses up to 12 mg/kg/day may provide improved efficacy and resistance prevention. Additionally, high-dose daptomycin has demonstrated excellent safety. Together, these data suggest a role for high-dose daptomycin in staphylococcal IE patients who are severely ill, previously failed therapy with vancomycin, or possess a S. aureus isolate with an elevated vancomycin MIC.