The [FeFe]- and [NiFe]-hydrogenases catalyze reversible hydrogen oxidation and occur in a variety of microorganisms including a select number of lower eukaryotes. Physiologically these enzymes either function 1) to couple the utilization of reducing equivalents derived from the oxidation of hydrogen to drive energy yielding processes or 2) in recycling reduced electron carriers that accumulate during anaerobic fermentation through proton reduction. These enzymes exist with complex metal-containing active sites with unique non-protein metal ligands including carbon monoxide and cyanide. Since the reversible hydrogen oxidation would likely have been an important reaction in the early earth and the emergence of life, these unique active site metal-clusters have been suggested to be the earliest cofactors. Our studies focus on resolving the detailed structural features of these unique enzymes and the unique biochemical steps by which these catalytic sites are biochemically synthesized. As part of the NASA Astrobiology Biogeocatalysis Research Center at MSU we are using our detailed understanding the structural determinants of catalysis and our insights into hydrogenase active site biosynthesis as inspiration for the modification of iron-sulfur minerals in an attempt to bridge iron-sulfur enzyme reactivity with iron-sulfur mineral reactivity. These studies provide the basis for understanding the role of iron-sulfur minerals in the transition from the living to the non-living world. The understanding of hydrogenase catalysis at a fundamental level also provides the basis for harnessing and designing biomimetic and biohybrid solutions to alternative energy.