With the emergence of microbial resistance pathogens, new mechanisms of action in antibacterials have attracted researchers’ attention lately. This chapter discusses the mechanisms and types of quorum sensing (QS) inhibitors in Gram-positive and -negative bacteria. It illustrates all the reported data available in literature pertaining to the different natural and synthetic compounds that showed activity against the different quorum sensing pathways in bacteria. A systemic overview has been conducted by searching Pubmed, Medline, and the Cochrane Library, and data extraction of all quorum sensing inhibitors with their mechanisms of action have been collected. The chapter is divided into three major categories of molecules that target the QS pathway: (1) signaling oligopeptides in Gram-positive bacteria solely, (2) signaling AI-1 in Gram-negative bacteria solely, and (3) signaling AI-2 in both Gram-positive and -negative bacteria. The biological activity of the antagonists is mainly reported as Ki (the inhibitor constant 0) or IC50 (the concentration of an inhibitor where the response is reduced by half).