All pathogenic and nonpathogenic microbes are continuously exposed to environmental or endogenous reactive oxygen and nitrogen species, which can critically effect survival and disease. Iron-sulfur [Fe-S] cluster containing prosthetic groups provide the microbial cell with a unique capacity to sense and transcriptionally respond to diatomic gases (e.g. NO and O 2) and redox-cycling agents. Recent advances in our understanding of the mechanisms for how the FNR and SoxR [Fe-S] cluster proteins respond to NO and O 2 have provided new insights into the biochemical mechanism of action of the Mycobacterium tuberculosis (Mtb) family of WhiB [Fe-S] cluster proteins. These insights have provided the basis for establishing a unifying paradigm for the Mtb WhiB family of proteins. Mtb is the etiological agent for tuberculosis (TB), a disease that affects nearly one-third of the world's population. © 2012 Elsevier Ltd.