Methanosarcina acetivorans, a member of the methanogenic archaea, can grow with carbon monoxide (CO) as the sole energy source and generates, unlike other methanogens, substantial amounts of acetate and formate in addition to methane. Phenotypic analyses of mutant strains lacking the cooS1F operon and the cooS2 gene suggest that the monofunctional carbon monoxide dehydrogenase (CODH) system contributes to, but is not required for, carboxidotrophic growth of M. acetivorans. Further, qualitative proteomic analyses confirm a recent report (Lessner et al., Proc Natl Acad Sci USA, 103:17921-17926, 2006) in showing that the bifunctional CODH/acetyl-CoA synthase (ACS) system, two enzymes involved in CO₂-reduction, and a peculiar protein homologous to both corrinoid proteins and methyltransferases are synthesized at elevated levels in response to CO; however, the finding that the latter protein is also abundant when trimethylamine serves as growth substrate questions its proposed involvement in the reduction of methyl-groups to methane. Potential catabolic mechanisms and metabolic adaptations employed by M. acetivorans to effectively utilize CO are discussed.