Genomes of S. aureus strains vary substantially in two major ways. Firstly, most isolates can be classified into one of the dominant lineages, and secondly they can carry combinations and variations of mobile genetic elements (MGE). Lineages vary in the presence, absence or variation of hundreds of "core variable" genes, many of which encode for surface associated proteins that interact with host. More than ten human lineages dominate, while other lineages colonise non-human hosts. Lineages can be detected by MLST clonal complexes, spa type groups, RM types or specifically designed microarrays. Minor variation within lineages can occur but the stability of such changes is unknown; in most cases this variation does not represent the independent evolution of a "sub-lineage". MGE often encode resistance and virulence associated genes. MGE can be relatively stable, such as the SCCmec types, or can be highly unstable such as some phage which can move during the course of infection. Recombination between MGE is very common, and most have a mosaic structure. Horizontal transfer of MGE leads to the evolution of new strains causing new clinical challenges, such as VRSA. Blocking of horizontal transfer by restriction modification systems has probably delayed the emergence of more virulent and resistant strains, although populations that are highly susceptible to horizontal transfer have been identified in animals.The major drivers of evolution are likely to be host interactions and antibiotic use. There is substantial geographical variation in MRSA lineages and MGE. Several clones of MRSA have caused well characterised outbreaks or unique disease profiles (eg. E-MRSA, CA-MRSA, TW, ST398) and identification of these clones moving into new areas can be useful in predicting likely outcomes and justifying measures to prevent their spread. Proving the role of particular genetic markers in virulence, spread or survival has been more difficult, although resistance genes have had a major impact on our ability to control the spread of strains and treat infections.