Methods and compositions for preventing and treating Staphylococcus aureusinfection in a subject are disclosed.Therapeutic compositions for the methods comprise leukocidin E and/or Dproteins or polypeptides and anti-leukocidin E and/or Dantibodies. Methods of identifying inhibitors of LukE/D cytotoxicity andinhibitors of LukE/D-leukocyte binding are also disclosed.