Several antibiotics interfere with the enzymes that are involved in the synthesis and assembly of the bacteria cell wall, inducing cell lysis. Dörr et al. now report a novel stress response system used by Vibrio cholerae to counteract these effects. Using a transposon-based screen, they identified the sensor kinase–response regulator pair WigKR as necessary for tolerance to penicillin. Notably, WigKR was activated in response to cell wall damage induced by multiple antibiotics, and overexpression of WigR resulted in the upregulation of several genes involved in cell wall synthesis, including the entire peptidoglycan biosynthesis pathway. Furthermore, WigR seems to regulate cell length and volume, even in the absence of antibiotics. Although the signal responsible for the activation of WigKR remains to be identified, these data suggest that this two-component system controls cell wall homeostasis both during normal growth and in response to antibiotic exposure.