<p>Twenty years ago, an archaeal lineage capable of catalyzing nitrate-dependent anaerobic methane oxidation (n-damo) was identified. This archaeal lineage was originally grouped within the ANME-2d cluster, and later renamed as the <i>Methanoperedenaceae</i> family. Since then, researchers worldwide have advanced our understanding of the biology of this archaeal group by describing its phylogenetic diversity, versatile metabolic functions, unique kinetic and physiological properties, special growing patterns, extracellular electron transfer capability, and extrachromosomal genetic elements. In addition, the potential engineering and industrial applications of <i>Methanoperedenaceae</i> have been explored broadly, employing granular and biofilm platforms for wastewater treatment and other purposes. In this Review, we reflect on the history of <i>Methanoperedenaceae</i> research, covering both the biology and the potential applications, summarize main achievements and challenges, and propose avenues for future research and applications.</p>