Within a given microbial population, a small subpopulation known as dormant persister cells exists. This persistence property ensures the survival of the population as a whole in the presence of lethal factors. Although persisters are highly important in antibiotic therapy, the mechanism for persistence is still not thoroughly understood. We show here that the cariogenic organism Streptococcus mutans forms persister cells showing noninherited multidrug tolerance. We demonstrated that the ectopic expression of the type II toxin-antitoxin systems, MazEF and RelBE, caused an increase in the number of persisters. In a search for additional persistence genes, an expression library was constructed, and several clones exhibiting a significant difference in persister formation after prolonged antibiotic treatment were selected. The candidate persister genes include genes involved in transcription/replication, sugar metabolism, cell wall synthesis, and energy metabolism, clearly pointing to redundant pathways for persister formation. We have previously reported that the S. mutans quorum-sensing peptide, CSP pheromone, was a stress-inducible alarmone capable of conveying sophisticated messages in the bacterial population. In this study, we demonstrate the involvement of the intraspecies quorum-sensing system during the formation of stress-induced multidrug-tolerant persisters. To the best of our knowledge, this is the first study reporting the induction of bacterial persistence using a quorum-sensing regulatory system.