This abstract describes the involvement of nickel enzymes in two CO2 reduction pathways: methanogenesis and acetate synthesis. Methanogenic microbes catalyze CO2 reduction to methane. Methyl-coenzyme M reductase (MCR) catalyzes the final step of methanogenesis. At the active site of MCR is coenzyme F430, a nickel tetrapyrrole. Recent studies have identified an alkyl-nickel(III) complex that can be converted to the thioether. Recent results will be described that provide evidence for the intermediacy of an alkylnickel species in anaerobic methane oxidation and methanogenesis. Many anaerobic microbes use the Wood-Ljungdahl pathway to reduce CO2 or CO to acetyl-CoA, which is converted to acetic acid and ATP. The key enzyme in this process is CO dehydrogenase/acetyl-CoA synthase (CODH/ACS), a bifunctional enzyme that reduces CO2 to CO and catalyzes the condensation of CO with a methyl group and CoA to generate acetyl-CoA. This enzyme features two novel Ni-metallocenters (a NiFe4S4 cluster and a dinickel site bridged to a Fe4S4 cluster), two Fe4S4 clusters, and a channel that connects the site of CO2 reduction on CODH to the site of acetyl-CoA synthesis on ACS. Recent studies will be described that provide insight into the nature of acid-base chemistry at the CODH active site, into the design of the channel, and into the mechanism of acetyl-CoA synthesis.