The anode and cathode potentials determine the overall performance of a microbial fuel cell (MFC). Thus far, research has focused on understanding the performance of individual electrodes, but there has been no investigation of how the anode or cathode potential changes as a function of the other. This study demonstrates for the first time that interplay exists between the anode and cathode electrodes, a phenomenon whereby reduction of voltage losses at one electrode increases voltage losses at the other. With our experimental data and results from the literature, a model was developed to quantify the interplay at theoretical and applied levels for wastewater treatment. The cause of the interplay was attributed to the reactant/product concentration gradient that exists between the bulk-catholyte-cathode and biofilm-anode electrode surfaces. These findings advance our fundamental understanding of MFCs and provide new insight into how to improve performance for wastewater treatment and energy production.