This review focuses on how microbes live on CO as a sole source of carbon and energy and with CO by generating carbon monoxide as a metabolic intermediate. The use of CO is a property of organisms that use the Wood-L jungdahl pathway of autotrophic growth. The review discusses when CO metabolism originated, when and how it was discovered, and what properties of CO are ideal for microbial growth. How CO sensing by a heme-containing transcriptional regulatory protein activates the expression of CO metabolism-linked genes is described. Two metalloenzymes are the cornerstones of growth with CO: CO dehydrogenase (CODH) and acetyl-CoA synthase (ACS). CODH oxidizes CO to CO2, providing low-potential electrons for the cell, or alternatively reduces CO2 to CO. The latter reaction, when coupled to ACS, forms a machine for generating acetyl-CoA from CO2 for cell carbon synthesis. The recently solved crystal structures of CODH and ACS along with spectroscopic measurements and computational studies provide insights into novel bio-organometallic catalytic mechanisms and into the nature of a 140 A gas channel that coordinates the generation and utilization of CO. The enzymes that are coupled to CODH/ACS are also described, with a focus on a corrinoid protein, a methyltransferase, and pyruvate ferredoxin oxidoreductase.