The increasing number of drug-resistant bacteria has brought great difficulties to clinical treatment, revealing the mechanism of drug resistance has become one of the basic ways to curb drug-resistant bacteria. Bacterial signaling system is the main channels of information exchange between bacteria and plays an important role in the regulation of bacterial drug resistance. This paper reviews the relationship between bacterial two-component system, quorum sensing signaling system, the second messengers, indole and other bacterial signal systems (molecules) and bacterial drug resistance, and summarizes the mechanisms and pathways of regulating drug resistance. It mainly includes regulating biofilm formation, regulating the activity of drug efflux system, activating antibiotic inactivation enzyme, improving drug-resistant gene expression level, promoting drug-resistant gene transfer, modifying cell wall structure, etc., which involves all links of bacterial drug resistance. Each signaling system can not only regulate drug resistance independently, but also cooperate with each other to form a regulatory network to regulate bacterial drug resistance at multiple levels. The above phenomenon indicates that bacterial signal transduction system plays a pivotal role in regulating bacterial drug resistance. Blocking or jamming the signaling system and cutting off the communication signals between bacteria could be a new strategy to curb the growing resistance of bacteria.