Pathogenic and commensal Escherichia coli isolates frequently contain defective alleles of the mutS and rpoS genes, located in a highly polymorphic segment of the chromosome. The environments leading to enrichment of rpoS mutations and the selective advantages of these mutants are becoming apparent. Unexpectedly, rpoS defects occur because of a basic design limitation in cellular regulation. Antagonistic pleiotropy results from the futile competition between different sigma factors associated with the RNA polymerase, and drives the elimination of RpoS (or sigma(S)) in environments requiring high levels of transcription that is dependent on RpoD (or sigma(D) or sigma(70)). Nutrient-limited environments provide an ideal breeding ground for rpoS mutations. By contrast, in other settings, increased stress resistance selects for restoration of rpoS function. Hence extensive polymorphism in the mutS-rpoS region is postulated to result from cycling between environments in which the functional or non-functional genes provide distinct fitness advantages.