Staphylococcus aureus can cause a wide variety of infections, ranging from minor skin infections to post-operative wound infections. Its adaptive power to antibiotics has resulted in the emergence of methicillin-resistant S. aureus (MRSA) in the beginning of the 1960s. Resistance to methicillin and all other beta-lactam antibiotics is caused by the mecA gene, which is situated on a mobile genomic island, the Staphylococcal Cassette Chromosome mec (SCCmec). Seven main SCCmec types, I to VII, have been distinguished. The most important methods used to study the molecular epidemiology of MRSA are pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), spa typing and SCCmec typing. These methods have been used to investigate the evolution of the MRSA clones that have emerged since the 1960s, and to study their worldwide dissemination. Early MRSA clones were hospital-associated (HA-MRSA). However, from the late 1990s, community-associated MRSA (CA-MRSA) has emerged. CA-MRSA harbors SCCmec type IV, V or VII, has a genetic background that is often distinct from HA-MRSA, and is often associated with the toxin Panton-Valentine leukocidin (PVL). However, the distinction between HA-MRSA and CA-MRSA is beginning to blur, and CA-MRSA is endemic in many US hospitals nowadays. This review describes the latest developments concerning the structure of SCCmec, the methods used to investigate the molecular epidemiology of MRSA, the molecular evolution of MRSA as well as the major challenges that are awaiting researchers in the near future.