The evolutionary development of bacterial cell-to-cell communication termed "quorum sensing" (QS) enabled coordinated behavioral efforts of bacterial populations, regulating processes such as biofilm formation and virulence factor expression, making QS modulation a prophylactic and therapeutic antivirulence target of considerable interest. QS signaling is mediated by three major classes of autoinducing molecules: N-acyl homoserine lactones (AHLs), oligopeptides, and autoinducer-2 (AI-2). Three main paradigms for QS modulators development are interference with the signal synthase, sequestration of the autoinducer, and antagonism of the receptor (the latter most studied to date). This Perspective focuses on the receptor antagonism approach toward QS modulators, reviewing their development from a medicinal chemical perspective with a focus on the methods and rationale used for their discovery and/or design and synthesis. It discusses agonists as well as antagonists of QS systems and includes relative potencies (EC50 values for agonists and IC50 values for antagonists) where given in the original literature, noting that strict comparisons may only be applied within a set of analogues examined in a particular assay due to variations in reporter assays. Finally, it discusses studies that have strived to establish QS as a viable target for the development of antimicrobial therapies.