Rapid emergence of antimicrobial resistance (AMR) has become a critical challenge worldwide. It is of great importance to understand how AMR is modulated genetically in order to explore new antimicrobial strategies. Recent studies have unveiled that microbial communication systems, which are known to play key roles in regulation of bacterial virulence, are also associated with the formation and regulation of AMR. These microbial cell-to-cell chemical communication systems, including quorum sensing (QS) and pathogen–host communication mechanisms, rely on detection and response of various chemical signal molecules, which are generated either by the microbe itself or host cells, to activate the expression of virulence and AMR genes. This article summarizes the generic signaling mechanisms of representative QS and pathogen–host communications systems, reviews the current knowledge regarding the roles of these chemical communication systems in regulation of AMR, and describes the strategies developed over the years for blocking bacterial chemical communication systems in disease control. The research progress in this field suggests that the bacterial cell-cell communication systems are a promising target not only for disease control but also for curbing the problem of microbial drug resistance.