The study investigates the role of quorum-sensing regulators, specifically LuxO and HapR, in controlling virulence gene expression in *Vibrio cholerae*. The ToxR signal transduction cascade is known to sense and integrate environmental information to control virulence, but this study reveals that quorum sensing also plays a significant role. Using an infant mouse model, the researchers found that a *luxO* mutant was severely defective in colonizing the small intestine. Gene array analysis showed that the ToxR regulon was repressed in the *luxO* mutant, and this repression was mediated by another negative regulator, HapR. LuxO was found to repress *hapR* expression early in log-phase growth, and constitutive *hapR* expression blocked ToxR-regulon expression. Additionally, LuxO and HapR regulate various cellular processes, including motility, protease production, and biofilm formation. The data suggest that quorum sensing modulates the expression of blocks of virulence genes in a reciprocal manner in *V. cholerae*. The study also highlights the evolutionary advantage of losing or down-regulating HapR, which may improve survival and colonization in the host by prolonging the expression of virulence factors and promoting detachment from the intestinal epithelium.The study investigates the role of quorum-sensing regulators, specifically LuxO and HapR, in controlling virulence gene expression in *Vibrio cholerae*. The ToxR signal transduction cascade is known to sense and integrate environmental information to control virulence, but this study reveals that quorum sensing also plays a significant role. Using an infant mouse model, the researchers found that a *luxO* mutant was severely defective in colonizing the small intestine. Gene array analysis showed that the ToxR regulon was repressed in the *luxO* mutant, and this repression was mediated by another negative regulator, HapR. LuxO was found to repress *hapR* expression early in log-phase growth, and constitutive *hapR* expression blocked ToxR-regulon expression. Additionally, LuxO and HapR regulate various cellular processes, including motility, protease production, and biofilm formation. The data suggest that quorum sensing modulates the expression of blocks of virulence genes in a reciprocal manner in *V. cholerae*. The study also highlights the evolutionary advantage of losing or down-regulating HapR, which may improve survival and colonization in the host by prolonging the expression of virulence factors and promoting detachment from the intestinal epithelium.