Staphylococcus aureus is a major human pathogen responsible for a wide diversity of infections ranging from localized to life threatening diseases. From 1961 and the emergence of methicillin-resistant S. aureus (MRSA), this bacterium has shown a particular capacity to survive and adapt to drastic environmental changes and since the beginning of the 1990s it has spread worldwide. Until recently, S. aureus was considered as the prototype of a nosocomial pathogen but it has now been recognized as an agent responsible for outbreaks in the community. Several recent reports suggest that the epidemiology of MRSA is changing. Understanding of pathogenicity, virulence and emergence of epidemic clones within MRSA populations is not clearly defined, despite several attempts to identify common molecular features between strains that share similar epidemiological and/or virulence behavior. These studies included: pattern profiling of bacterial adhesins, analysis of clonal complex groups, molecular genotyping and enterotoxin content analysis. To date, all approaches failed to find a correlation between molecular determinants and clinical outcomes. We hypothesize that the capacity of the bacterium to become more invasive or virulent is determined by genetics. The utilization of massively parallel methods of analysis is therefore ideal to study the contribution of genetics. Therefore, this article focuses on the entire genome including coding sequences as well as noncoding sequences. This high resolution approach allows the monitoring micro- and macroevolution of MRSA and identification of specific genomic markers of evolution of invasive or highly virulent phenotypes.