Accessory gene regulator (agr)-mediated quorum sensing plays a central role in staphylococcal pathogenesis. It primarily upregulates secreted virulence factors and downregulates cell surface proteins, thereby governing invasiveness of staphylococci and cell dispersal from biofilms. Except for α- and β-PSMs, which are directly controlled by AgrA, the effector functions of agr are primarily mediated by RNAIII, a regulatory RNA encoded by this operon. agr phenotype and expression considerably influence the chronicity of an infection. It has also been linked with altered susceptibility of Staphylococcus aureus against antibiotics. Four classes of S. aureus and Staphylococcus epidermidis AIPs exist based on sequence variation, and lead to inter-strain and species cross-inhibition. Certain agr classes have been associated with specific clonal complexes, disease syndromes and intermediate-susceptibility to glycopeptides. It is also being investigated as a prophylactic and therapeutic target. This article describes the presently available literature regarding the role of agr in S. aureus and S. epidermidis infections.