Two factors, climate change brought on by rising atmospheric CO2 levels and the accelerating shift toward renewable energy sources, have together worked to heighten interest in understanding how biological catalysts so effectively bring about the reduction of CO2 to formate, with potential applications for both bioremediation and energy storage. Most metal-dependent formate dehydrogenases, containing either molybdenum or tungsten in their active sites, function physiologically in the direction of formate oxidation to CO2, but it has become clear that many, if not all, are also effective in catalyzing the reverse reaction. In this chapter, we describe methods for isolating and characterizing these enzymes.