The ability of Staphylococcus aureus to rapidly acquire antibiotic resistance in the face of antimicrobial challenge has enabled it to remain an ongoing, significant human pathogen. Mechanisms behind the evolution of resistance in S. aureus are well documented, but the effects of these phenotypes upon virulence are less clear. By exploring available clinical and experimental data, we have shown that a number of the major steps in the evolution of antibacterial resistance in S. aureus have been accompanied by alterations in virulence. This review also highlights that further experimentation is required to fully elucidate the mechanisms involved in the interface between virulence and antibiotic resistance, with the intention of identifying novel preventative or therapeutic strategies for this important human pathogen.