MitoNEET is a newly discovered mitochondrial protein and a target of the TZD class of antidiabetes drugs. MitoNEET is homodimeric with each protomer binding a [2Fe-2S] center through a rare 3-Cys and 1-His coordination geometry. Both the fold and the coordination of the [2Fe-2S] centers suggest that it could have novel properties compared to other known [2Fe-2S] proteins. We tested the robustness of mitoNEET to mutation and the range over which the redox potential (E(M)) could be tuned. We found that the protein could tolerate an array of mutations that modified the E(M) of the [2Fe-2S] center over a range of ∼700 mV, which is the largest E(M) range engineered in an FeS protein and, importantly, spans the cellular redox range (+200 to -300 mV). These properties make mitoNEET potentially useful for both physiological studies and industrial applications as a stable, water-soluble, redox agent.