Bacteria utilize a distinct subfamily of sigma factors to regulate extra cytoplasmic function (thus termed as ECF subfamily). Eubacteria appear to have evolved to incorporate extensive genetic diversity into their repertoire of ECF sigma factors (some species have more than 60 ECF sigma factors), while maintaining three major themes common to all members including: (1) they regulate and respond to extracytoplasmic functions; (2) they are themselves regulated by anti-sigma and/or anti-anti-sigma factors; and (3) most of them control a relatively small regulon. The cell wall is the first bacterial structure that comes in contact with the host during infection by pathogenic bacteria. The cell wall components are often associated with functions related to host cell invasion. It is therefore, likely that the ECF sigma factors regulate the bacterial response to host insult. Moreover, in some cases, virulence factors have been shown to be regulated directly by the ECF sigma factors. Unfortunately, this facet of the ECF sigma factors has not been an important area of study by researchers. The present review attempts to highlight the important role played by ECF sigma factors in bacterial pathogenesis and highlights several areas of future study involving the genetics of ECF sigma factors vis-à-vis bacterial pathogenesis.