All organisms possess a diverse set of genetic programs that are used to alter cellular physiology in response to environmental cues. The gram-negative bacterium Escherichia coli induces a gene regulatory network known as the “SOS response” following exposure to DNA damage, replication fork arrest, and a myriad of other environmental stresses. For over 50 years, E. coli has served as the paradigm for our understanding of the transcriptional and physiological changes that occur after DNA damage. In this chapter, we summarize the current view of the SOS response and discuss how this genetic circuit is regulated. In addition to examining the E. coli SOS response, we include a discussion of the SOS regulatory networks found in other bacteria to provide a broad perspective on the mechanism and diverse physiological responses that ensueto protect cells and maintain genome integrity.