Cyclic amp receptor protein (CRP) is a global transcriptional factor in many prokaryotes, capable of governing nearly half of the total genes in Escherichia coli. Through the method of error-prone PCR or DNA shuffling, we can first obtain CRP mutant library and then get the expected cell phenotype with enhanced resistance. In this article, we reviewed the following desired phenotype: enhanced tolerance towards oxidative stress, improved osmotolerance, enhanced organic solvent (toluene) tolerance, improved acetate tolerance of E. coli fermentation and improved ethanol tolerance during bio-ethanol production. We then concluded that CRP can also be applied in other host cells to get desired phenotypes. Last, we predicted potential applications of mutant CRP transcriptional factor.