The oxo-acid:ferredoxin oxidoreductease (OFOR) superfamily represents a large and ancient enzyme class that is capable of the reversible interconversion of CO2 and other C-C bond containing molecules. Members of the family are responsible for both oxidizing oxo-acids such as pyruvate (PFOR), to produce electrons that are taken up in a ferredoxin (Fd) pool, and yield acetyl-CoA. However, OFORs must also operate in the reductive direction, such as the OGOR enzyme that produces oxo-glutarate from CO2 and succinyl-coA, and PFOR when it must act as a pyruvate synthase. Typical OFOR family members have three [4Fe—4S] clusters that wire the Fd redox pool with the thiamin pyrophosphate (TPP)-based active site. Here, we have hypothesized that the various physiological roles of individual OFOR family members may correlate to the redox traits (potentials, and electron transfer rates) associated with the [4Fe—4S] clusters. To pursue that question, we have engaged in a comparative analysis of multiple OFOR family members, through enzymological, electrochemical and spectroscopic approaches. In this presentation we report on: (1) the critical role that the identity of a redox carrier may play in influencing the reactivity of the OFOR enzyme; (2) the remarkably similar redox potentials that predict a novel ‘flat’ thermodynamic landscape of electron transfer between the OFOR [4Fe—4S] clusters; and (3) that the Fd proteins themselves which serve as redox carriers may be much more diverse than historically considered.