Transposon-mediated “directed” mutations occur at higher frequencies when beneficial than when detrimental and relieve the stress that causes them. The first and best-studied example involves regulation of Insertion Sequence-5 (IS5) insertion into a specific activating site upstream of the glycerol utilization operon in Escherichia coli, glpFK. This event promotes high level expression of the glpFK operon, allowing glycerol utilization in wild type cells under inhibitory conditions. The phosphoenolpyruvate-dependent, sugar transporting, phosphotransferase system (PTS) influences this process by regulating cytoplasmic glycerol-3-phosphate and cyclic AMP concentrations. Insertion frequencies are determined by IS5-specific tetranucleotide target sequences in stress-induced (DNA) duplex destabilization (SIDD) structures counteracted by two DNA binding proteins, GlpR and Crp which directly inhibit insertion, responding to cytoplasmic glycerol-3-phosphate and cyclic AMP, respectively. Expression of the E. coli master regulator of flagellar gene control, flhDC, is subject to activation by IS elements by a directed mechanism, and zinc-induced transposon-mediated zinc resistance has been demonstrated in Cupriavidus metallidurans. The use of DNA conformation and DNA binding proteins to control transposon hopping also occurs in eukaryotes.