[4Fe-4S] clusters are ubiquitous in biology and are crucial to the more salient processes in energy metabolism, serving as intermediates in inter- and intramolecular electron transfer pathways. The [4Fe-4S] clusters are more prevalent, serving a variety of functions, and can remarkably adopt a surprising range of reduction potentials spanning more than 1 V. The characteristics of the environment, including charge, solvent access, and geometric distortion, finely modulate the reduction potential of iron/sulfur clusters. However, prior research has not yet systematically addressed cause and effect. In this work, we conducted a thorough theoretical assessment of how charge distribution and structural distortion contribute to the full range of reductions exhibited by biological [4Fe-4S] clusters. The work shows that the most significant contributions can be predicted for electrostatic interactions, which are directionally biased.