Daptomycin is the first new natural-product antibiotic launched in a generation. It was licensed first for skin and soft tissue infections (SSTIs) and, more recently, for staphylococcal bacteraemia and endocarditis. Further clinical trials are in progress, some investigating performance in subsets of SSTIs while others, more interestingly, are evaluating efficacy in enterococcal endocarditis and neutropenic fevers—settings where the compound’s bactericidal activity is potentially advantageous. There is a need for further trials in bone and joint infections. On the negative side, there are several reports of mutational resistance emerging during the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, mostly in settings with a heavy bacterial load, and there is a need to determine whether higher dosages or combination regimens will reduce this risk. A few patients have already been treated with doses of up to 12 mg/kg. Lastly, daptomycin is entering a market increasingly crowded with new anti-Gram-positive agents. More work is required to establish those settings where daptomycin and other new compounds offer real advantages over established glycopeptides and over each other. There is presently a paradox whereby vancomycin is agreed to be less than ideal, with outcomes impaired against MRSA with modestly raised MICs, but where new agents have yet to demonstrate unequivocal superiority.