The accessory gene regulator (agr) quorum-sensing system is arguably the most important regulator of Staphylococcus virulence. The agr-system serves a crucial role in pathogenesis by triggering substantive gene expression alterations to up-regulate the production of a wide variety of virulence determinants such as exoenzymes (proteases, lipases, nucleases) and downregulate the expression of surface binding proteins. Accordingly, the agr-system represents a compelling target for the development of antivirulence therapeutics as potential adjuncts, or alternatives, to conventional bactericidal and bacteriostatic antibiotics. Despite this potential, to date, no agr-system inhibitors have progressed to the clinic; however, several promising lead compounds have been identified through screens of synthetic and natural product libraries. On the basis of the molecular components within the agr-system, the current contingent of regulating compounds can be clustered into three broad groups, AgrA-P3 activation inhibitors, AgrB-AgrD processing inhibitors, and AgrC-AIP interaction inhibitors. This review aims to provide an overview of the development, structure-activity-relationships, and limitations of compounds within each of these groups in addition to the current opportunities for developing next-generation anologs.