The pathogenic potential of Staphylococcus aureus is well known as well as its role both in nosocomial and community-acquired infections. When penicillin was introduced by mid '40s, S. aureus was almost 94% susceptible to this drug. Widespread resistance to penicillin developed in the '50s, followed by resistance to semi synthetic penicillins in the '60s and '70s. Since then, strains of methicillin-resistant Staphylococcus aureus and methicillin-resistant coagulase-negative staphylococci have spread worldwide. The prevalence of methicillin-resistant S. aureus varies geographically. In our country it reaches nearly 50%. Methicillin resistance in Staphylococci develops due to an additional penicillin binding protein, PBP2a, which is encoded by gene mecA, the responsible of methicillin resistance. Methicillin resistance in Staphylococcus aureus and in coagulase-negative staphylococci represents a serious problem both for the microbiologist and the physician. A special feature of methicillin resistance is its heterogeneous nature with different levels of resistance. Most clinical isolates show a heterogeneous pattern under routine growth conditions. The high prevalence of methicillin-resistant staphylococci compromises the use of semi synthetic penicillins for empiric treatments in many institutions, thus increasing the use of vancomycin. Until 1996, glycopeptides were almost universally active against S. aureus but it was then that the first glycopeptide-intermediate S. aureus (GISA) was described and isolated in Japan, followed by France and USA. The exact mechanism involved has not been elucidated yet, although vancomycin resistance is associated with increased wall synthesis.