In Gram-positive bacteria such as and the coagulase-negative staphylococci (CoNS), the accessory gene regulator () is a highly conserved but polymorphic quorum-sensing system involved in colonization, virulence and biofilm development. Signalling via depends on the interaction of an autoinducing peptide (AIP) with AgrC, a transmembrane sensor kinase that, once phosphorylated activates the response regulator AgrA. This in turn autoinduces AIP biosynthesis and drives target gene expression directly via AgrA or via the post-transcriptional regulator, RNAIII. In this review we describe the molecular mechanisms underlying the -mediated generation of, and response to, AIPs and the molecular basis of AIP-dependent activation and inhibition of AgrC. How the environment impacts on functionality is considered and the consequences of dysfunction for infection explored. We also discuss the concept of AIP-driven competitive interference between and the CoNS and its anti-infective potential.