Methanogenesis is a mode of energy metabolism found in anaerobic microorganisms within the archaeal domain of life. All methanogens use the enzyme methyl-coenzyme M reductase (MCR) to produce methane. MCR is an exquisitely oxygen-sensitive enzyme that catalyzes a unique radical-based reaction, which requires many unusual cofactors and coenzymes. A persistent and increasing interest in MCR from both climate and energy perspectives has led to the development of new tools to study methanogens. These tools have, in turn, led to a flourish of new developments pertaining to MCR assembly and activation of late. In this review, we highlight the discovery of new proteins involved in MCR biogenesis in vivo, discuss the major missing pieces in our understanding, and present some of the newest technological developments enabling this ongoing work.