This study describes a novel method for controlling applied voltage in a microbial electrolysis cell (MEC). It is demonstrated that the rate of hydrogen production could be maximized without excessive energy consumption by minimizing the apparent resistance of the MEC. A perturbation and observation algorithm is used to track the minimal apparent resistance by adjusting the applied voltage. The algorithm was tested in laboratory-scale MECs fed with acetate or synthetic wastewater. In all tests, changes in MEC performance caused by the variations in organic load, carbon source properties, and hydraulic retention time were successfully followed by the minimal resistance tracking algorithm resulting in maximum hydrogen production, while avoiding excessive power consumption. The proposed method of real-time applied voltage optimization might be instrumental in developing industrial scale MEC-based technologies for treating waste-waters with varying composition. Crown Copyright (C) 2011, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.