Coagulase-positive (Staphylococcus aureus) and coagulase-negative staphylococci are gram-positive cocci appearing in clusters that are important causes of infection, primarily of the bloodstream, native and prosthetic cardiac valves, other implanted devices, and skin. Their progressively reduced susceptibility to penicillin, methicillin, and glycopeptides makes treatment of staphylococcal infections difficult. This article reviews the current status and the future perspectives for the therapy of infections caused by S. aureus and coagulase-negative staphylococci, such as S. epidermidis.