Extracytoplasmic function σ factors (ECFs) represent a fundamental and widely distributed principle of bacterial signal transduction that connects the perception of a stimulus (input) with the induction of an appropriate set of genes (output). In recent years, comparative genomics analyses have not only allowed a systematic and functional classification of ECFs but also indicated the presence of numerous novel and widely conserved mechanisms of ECF-dependent signaling. Some of these novel systems have been experimentally characterized and uncovered unique features not previously observed. These studies demonstrate that ECF-dependent signaling is much more versatile and diverse than has been appreciated before. They also indicate that the majority of mechanisms that regulate ECF activity still remain to be discovered and characterized.