Staphylococcus aureus is widely appreciated as a pathogen, despite the fact that this microorganism is usually a benign colonizer of the host, rarely if ever causing infection. However, this bacterium, in response to changing environments, will occasionally switch from a commensal to a lethal pathogen. S. aureus uses an array of two-component signal transduction systems, winged-helix transcription proteins, and alternate sigma factor to create an intricate network of regulation in response to environmental change/stimuli. The interactions between members of this large cast of regulatory elements are beginning to be appreciated. Predicated upon recent genomic data, this review focuses on how this regulatory apparatus functions to control the expression of the multitude of virulence factors this "Jekyl and Hyde" organism produces.