A tantalizing question in microbial physiology is the inter-dependence and evolutionary potential of cellular stress response across multiple environmental dimensions. To address this question, we comprehensively characterized the cross-stress behavior of wild-type and evolved Escherichia coli populations in five abiotic stresses (n-butanol, osmotic, alkaline, acidic, and oxidative) by performing genome-scale genetic, transcriptional and growth profiling, thus identifying 18 cases of

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... s protection and one case of cross-stress vulnerability. We identified 18 cases of cross-stress protection and one case of cross-stress vulnerability, along with core and stress-specific networks. We tested several hypotheses regarding the effect of the stress order, stress combinations, mutation reversal and varying environments to the evolution and final cellular fitness of the respective populations. Our results argue of a common systems-level core of the stress response with several crucial implicated pathways that include metal ion binding and glycolysis/gluconeogenesis that is further complemented by a stress-specific expression program.