We have examined the effect of a wide range of antimicrobial compounds (antibiotics and biocides) on the growth of various strains of Escherichia coli which vary in their ability to produce ppGpp and sigma s. We conclude that strains able to synthesize ppGpp, either in a RelA- or SpoT-dependent manner, possess a greater resistance to antimicrobial compounds compared with strains that cannot produce ppGpp. Investigation of an E. coli strain, unable to produce sigma s, and an isogenic parent strain, suggests that there is a requirement for this sigma factor in increased expression of intrinsic resistance. We propose that ppGpp is required to induce production of sigma s, which in turn directs gene expression of intrinsic resistance determinants.