Methyl-coenzyme M reductase (MCR) is the key enzyme in the biological formation of methane (methanogenesis), a potent greenhouse gas and biofuel. Homologs of MCR are also found in archaea that catalyze the anaerobic oxidation of methane (AOM) and other short-chain alkanes. The activity of MCR is critically dependent on the nickel-containing tetrapyrrole, coenzyme F430. In addition to housing F430, the active site of MCR contains several unprecedented post-translational modifications (PTMs), including 2-(S)-methylglutamine, 5-(S)-methylarginine, 3-methylhistidine, S-methylcysteine, and thioglycine residues. Because of its unique activity, MCR holds much promise for use in methane bioconversion strategies. However, a lack of genetic and biochemical information about the biosynthesis of coenzyme F430 and the PTM of MCR have hampered metabolic engineering efforts utilizing this enzyme. This seminar will describe current progress in the understanding of MCR maturation and the production of holo MCR in heterologous, non-methanogenic hosts.