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The envelope demarcates the boundary between bacterial cell and its environment, providing a place for bacteria to transport nutrients and excrete metabolic waste, while buffering external environmental stress. Envelope stress responses (ESRs) are important tools for bacteria to sense and repair envelope damage. In this review, we discussed evidence that indicates the important role of the Cpx ESR in pathogen-host interactions, including environmental stress sensing and responses, modulation of bacterial virulence, antimicrobial resistance, and inter-kingdom signaling.