Significance: Heme is an important prosthetic group required in a wide array of functions, including respiration, photosynthesis, metabolism, O 2 transport, xenobiotic detoxification, and peroxide production and destruction, and is an essential cofactor in proteins such as catalases, peroxidases, and members of the cytochrome P450 superfamily. Importantly, bacterial heme-based sensor proteins exploit the redox chemistry of heme to sense environmental gases and the intracellular redox state of the cell. Recent Advances: The bacterial proteins FixL (Rhizobium ssp.), CooA (Rhodospirillum rubrum), EcDos (Escherichia. coli), RcoM (Burkholderia xenovorans), and particularly Mycobacterium tuberculosis (Mtb) DosS and DosT have emerged as model paradigms of environmental heme-based sensors capable of detecting multiple gases including NO, CO, and O2. Critical Issues: How the diatomic gases NO, CO, or O2 bind to heme iron to generate Fe-NO, Fe-CO, and Fe-O2 bonds, respectively, and how the oxidation of heme iron by O2 serves as a sensing mechanism that controls the activity of key proteins is complex and largely unclear. This is particularly important as many bacterial pathogens, including Mtb, encounters three overlapping host gases (NO, CO, and O2) during human infection. Future Directions: Heme is an important prosthetic group that monitors the microbe's internal and external surroundings to alter signal transduction or enzymatic activation. Modern expression, metabolomic and biochemical technologies combined with in vivo pathogenesis studies should provide fresh insights into the mechanism of action of heme-based redox sensors. © 2012 Mary Ann Liebert, Inc.