Staphylococcus aureus is an opportunistic pathogen. In response to changing host environments, this bacterium has the capability to switch on selective sets of genes to enhance its chances for survival. This switching process is precisely controlled by global regulatory elements. There are two major groups of global regulatory elements in S. aureus, including two-component regulatory systems (TCRSs) and the SarA protein family. Presumably, the sensor proteins of the 16 TCRSs in S. aureus provide external sensing, while the response regulators, in conjunction with alternative transcription factors and the SarA protein family, function as effectors within the intricate regulatory network to respond to environmental stimuli. Sequence alignment and structural data indicate that the SarA protein family could be subdivided into three subfamilies: (1) single-domain proteins; (2) double-domain proteins; and (3) proteins homologous to the MarR protein family. Recent data using reporter gene fusions in animal models, have confirmed distinct expression profiles of selected regulatory and target genes in vitro vs. in vivo.