Methanogens are masters of CO₂ reduction. They conserve energy by coupling H₂ oxidation to the reduction of CO₂ to CH₄, the primary constituent of natural gas. They also generate methane by the reduction of acetic acid, methanol, methane thiol, and methylamines. Methanogens produce 10⁹ tons of methane per year and are the major source of the earth’s atmospheric methane. Reverse methanogenesis or anaerobic methane oxidation, which is catalyzed by methanotrophic archaea living in consortia among bacteria that can act as an electron acceptor, is responsible for annual oxidation of 10⁸ tons of methane to CO₂. This chapter briefly describes the overall process of methanogenesis and then describes the enzymatic mechanism of the nickel enzyme, methyl-CoM reductase (MCR), the key enzyme in methane synthesis and oxidation. MCR catalyzes the formation of methane and the heterodisulfide (CoBSSCoM) from methyl-coenzyme M (methyl-CoM) and coenzyme B (HSCoB). Uncovering the mechanistic and molecular details of MCR catalysis is critical since methane is an abundant and important fuel and is the second (to CO₂) most prevalent greenhouse gas.