A broad variety of infections, ranging from minor infections of the skin to post-operative wound infections can be caused by Staphylococcus aureus. The adaptive power of S. aureus to antibiotics leaded, in the early 1960s, to the emergence of methicillin-resistant S. aureus (MRSA). The cause of resistance to methicillin and all other beta-lactam antibiotics is the mecA gene, which is situated on a mobile genetic element, the staphylococcal cassette chromosome mec (SCCmec). Seven major variants of SCCmec, type I to VII, are distinguished. The most important techniques used to investigate the molecular epidemiology of S. aureus are pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST), S. aureus protein A (spa) typing and SCCmec typing (only for MRSA). These techniques have been used to study the evolution of the MRSA clones that have emerged since the early 1960s, and to study their subsequent worldwide dissemination. The early MRSA clones were hospital-associated (HA-MRSA). However, from the late 1990s, community-associated MRSA (CA-MRSA) clones emerged worldwide. CA-MRSA harbors SCCmec type IV, V or VII, the majority belong to other S. aureus lineages compared to HA-MRSA, and CA-MRSA is often associated with the presence of the toxin Panton-Valentine leukocidin (PVL). However, during recent years, the distinction between HA-MRSA and CA-MRSA has started to disappear, and CA-MRSA is now endemic in many US hospitals. MRSA probably originated trough the transfer of SCCmec into a limited number of methicillin-sensitive S. aureus (MSSA) lineages. This review describes the latest observations about the structure of SCCmec, the techniques used to study the molecular epidemiology and evolution of S. aureus as well as some challenges that researchers face in the future.