Microbial fuel cells (MFCs) are capable of producing electricity while cleaning wastewater. The goal of this work is to optimize an MFC-based wastewater treatment process to maximize the amount of wastewater that is cleaned. An MFC mathematical model is used to compare different operating modes and reactor configurations. The following observations are made based on the model analysis: (i) the ratio between the anodophilic and methanogenic populations can be controlled by the electrical load; (ii) coexistence of the two populations decreases reactor performance; (iii) MFCs that are connected in series always improve treatment efficiency; and (iv) influent and effluent concentrations can be used to define the best series configuration.