Methyl-coenzyme M reductase (MCR) is the key enzyme in pathways for the biological formation and anaerobic oxidation of methane. MCR is an α2β2γ2 heterohexamer with two active sites that each contain several unprecedented post-translational modifications (PTMs) and a unique nickel corphinoid prosthetic group, coenzyme F430. The active form of MCR (MCRred1) contains F430 in the reduced, Ni(I) form, and catalyzes the conversion of methyl-coenzyme M and coenzyme B to the CoB-S-S-CoM heterodisulfide and methane. Current progress in understanding the biosynthesis and insertion of coenzyme F430 and the maturation and reductive activation of MCR is presented. As methane is a potent greenhouse gas and biofuel, these studies have potential applications in the development of novel inhibitors of methanogenesis and in the heterologous assembly of MCR for use in natural gas conversion strategies.