A highly adaptive commensal organism, Staphylococcus aureus, possesses an array of genes that allow the bacterium to survive and grow in a wide variety of niches. Several of these niches are known to be or become anaerobic during the course of an infection; additionally, biofilms that develop, commonly on implanted medical devices, become anaerobic. The metabolic capability of S. aureus provides the organism with the essential nutrients needed to continue to grow, divide, and thwart the host immune system in the presence or absence of oxygen. In order to utilize the ATP-producing pathways and maintain cellular health S. aureus has evolved a series of regulatory systems that regulate these ATP-producing pathways. In this review, we discuss the protein signaling systems that sense, indirectly and directly, anaerobic conditions, their sensory mechanisms and signals, and outline the genes that are altered due to the absence of oxygen and the subsequent response by the bacterial cell. The switch from aerobic to anaerobic growth in S. aureus is complex and highly regulated, with some metabolic pathways regulated by multiple regulatory systems to ensure maximal utilization of each pathway and substrate.