Staphylococcus aureus is a Gram-positive pathogen capable of causing a wide array of infections owing, in large part, to the coordinated expression of an extensive repertoire of virulence factors. Our laboratory and others have shown that the expression of these factors can occur post-transcriptionally at the level of mRNA turnover and is mediated by ribonucleases, RNA-binding proteins, and regulatory RNA molecules. Moreover, S. aureus harbors the ability to alter the stability of its mRNA titers in response to physiological stresses, including antibiotic exposure. Although ongoing studies are attempting to identify the molecular components that modulate S. aureus mRNA turnover, innovative approaches to target these essential processes have established a novel group of targets for therapeutic development against staphylococcal infections.