Structurally and functionally diverse CO dehydrogenases are key components of various energy-yielding pathways in aerobic and anaerobic microbes from the Bacteria and Archaea domains. Aerobic microbes utilize Mo-Fe-flavin CO dehydrogenases to oxidize CO in respiratory pathways. Phototrophic anaerobes grow by converting CO to H2, a process initiating with a CO dehydrogenase that contains nickel and iron-sulfur centers. Acetate-producing anaerobes employ a nickel/iron-sulfur CO dehydrogenase to synthesize acetyl-CoA from a methyl group, CO, and CoA. A similar enzyme is responsible for the cleavage of acetyl-CoA by anaerobic Archaea that obtain energy by fermenting acetate to CH4 and CO2. Acetotrophic sulfate reducers from the Bacteria and Archaea also utilize CO dehydrogenase to cleave acetyl-CoA yielding methyl and carbonyl groups. These microbes obtain energy for growth via a respiratory pathway in which the methyl and carbonyl groups are oxidized to CO2, and sulfate is reduced to sulfide.