One of the main performance challenges in microbial electrochemical cells (MXCs) is the low voltage efficiency in comparison to other fuel and electrolysis cells.  For example, in the case of microbial fuel cells (MFCs), a theoretical maximum of 1.1 V is available when coupling acetate oxidation at the anode to O₂ reduction at the cathode, while at current densities of > 5 A m^-2, only < 0.3 V is produced, representing > 0.8 V of overpotential. Similarly, although the theoretical applied voltage in microbial electrolysis cells (MECs) is only 0.14 V, the actual applied voltage can be as high as 1.2 V, representing close to 1 V of overpotential. Thus, there is a need to consider design and operation tactics for MXCs that help reduce the overall overpotential in the system. In this study, we aimed to improve the design and operation of MECs to achieve current densities >10 A m^-2 with reduced applied voltages, using a thorough analytical framework involving electrochemical techniques such as chronoamperometry, voltammetry and electrochemical impedance spectroscopy. We developed a design that allows high surface area for the anode using carbon fibers, but without creating a large distance between the anode and the cathode (<0.5 cm) to reduce Ohmic overpotential. We determined that Ohmic overpotential, at current densities >10 A m^-2 remained <0.1 V even when using an anion exchange membrane to separate the anode and the cathode. We observed the largest overpotential from cathode related phenomena. The increase in pH in the cathode chamber, often to ~13, results in >0.3 V of Nernstian concentration overpotential. We showed how by adding CO₂ to the cathode, this overpotential could be reduced to negligible.  We revealed that the benefit of CO₂ was primarily on the pH and not necessarily on the cathode activation overpotential through electrochemical impedance spectroscopy on the cathode.  We also tested two different cathode materials (stainless steel and nickel) to compare the cathode activation overpotentials.  Overall, through our design and operation improvements, we were able to reduce the applied voltages from 1.1 to ~0.85 V, at 10 A m^-2.  However, the cathode overpotential is still a major problem in our reactor design possibly due to local concentration gradients on cathodes, resulting in Nernstian concentration overpotential.  To overcome this, it is required to optimize mass transport further between the anode and the cathode, possibly through novel designs and/or improved hydrodynamics at the local surfaces, estimating cathode overpotential ~0.2 V.  Then, we estimate that the total applied voltage in MECs at high current densities (e.g. >10 A m^-2) could be reduced as low as 0.7 V.