Methane is a potent greenhouse gas, a relatively clean burning fossil fuel, but also a renewable biofuel when biologically produced from waste treatment plants. Most (~70%) of the global methane emission comes from methanogenic archaea, namely methanogens that produce methane from simple substrates such as H2/CO2, formate, acetate, methanol, and other methylated compounds. Methanogens are found across all corners of the earth, including but not limited to wetlands, animals and humans, rice fields, landfills, sewage, ocean, termites, and hydrothermal vents. Their extensive adaptations to such a wide range of habitats predict a cross-boundary significance of methanogens in many areas such as the environment, energy, agriculture, biotechnology, and human and animal health. The goal of this Research Topic is to offer a forum that highlights the cross-boundary significance of methanogens by bringing together methanogen research from diverse settings to one place. This cross-boundary significance is currently underappreciated but imperative to collectively understanding and helping to solve some of the biggest and most urgent challenges humanity is facing such as global warming, food and energy insecurity, pollution, and disease. As a more potent and shorter-lived greenhouse gas than CO2, methane has moved to the center stage in our efforts in rapidly combating climate change. Presumably, methanogens and their associated microbes may have been forced into a positive feedback loop to fuel the sharp rise of methane in recent years. On the other hand, methanogens are considered keystone species in the ecosystem, which are vital to the stability of the natural biome therein. However, the roles of methanogens as keystone species across their habitats are underexplored. Moreover, the role of methanogens in human and animal intestinal microbiomes have been reconsidered with evidence for links to disease and impact on nutrition. Last but not the least, methanogens are emerging as a cell factory model for green manufacturing, because of their abilities to convert CO2 to valuable biochemicals. Further efforts in the bioengineering of methanogens have the potential to expand their commercial application from waste treatment to biomanufacturing. We welcome both basic and translational studies relevant to methanogens from any setting. Studies with a focus on methanogens are highly encouraged, and manuscripts having methanogens as a significant component are also welcome. All studies should emphasize and envisage their implications in understanding and/or solving one or more challenges humanity is facing. To encourage submissions from multiple disciplines, this Research Topic is cross-listed with a number of Frontiers journals and sections. Manuscripts in the forms of Original Research, Review (including systematic and mini review), Methods, Hypothesis and Theory, and Perspectives are all welcome. Manuscript summary submissions are highly encouraged but all manuscripts submitted prior to the manuscript submission deadline will receive full consideration. This Research Topic is dedicated to Dr. William Barny Whitman, Emeritus Professor of Microbiology at the University of Georgia, Athens, GA. His 40+ years (and still counting) of productive research in methanogens, roseobacter, and other prokaryotes have contributed to and will continue to inspire new discoveries in the cross-boundary significance of both archaea and bacteria – the unseen majority. COI Statement: S.K.-M.R.R. is co-founder of Arkeon GmbH. M.P. is a consultant for Bausch Health, Ferring Pharmaceuticals Inc., Salvo Health, and Vivante Health Inc.