Background: The major biological form of selenium is that of the co-translationally inserted amino acid selenocysteine (Sec). In Archaea, the majority of proteins containing Sec, selenoproteins, are involved in methanogenesis. However, the function of this residue is often not known because selenium-independent homologs of the selenoproteins can be employed, sometimes even in one organism. Scope of review: This review summarizes current knowledge about the selenoproteins of Archaea, the metabolic pathways where they are involved, and discusses the (potential) function of individual Sec residues. Also, what is known about the “archaeal” way of selenoprotein synthesis, and the regulatory mechanism leading to the replacement of the selenoproteins with selenium-independent homologs, will be presented. Where appropriate, similarities with (and differences to) the respective steps employed in the other two domains, Bacteria and Eukarya, will be emphasized. Major conclusions: Genetic and biochemical studies guided by analysis of genome sequences of Sec-encoding archaea has revealed that the pathway of Sec synthesis in Archaea and Eukarya are principally identical and that Sec insertion in Eukarya probably evolved from an archaeal mechanism employed prior to the separation of the archaeal and eukaryal lines of decent. General significance: In light of the emerging close phylogenetic relationship of Eukarya and Archaea, archaeal models may be highly valuable tools for unraveling “eukaryotic” principles in molecular and cell biology.