Microbial Fuel Cells (MFCs) are capable of producing electricity while cleaning wastewater. This novel technology can replace energy-consuming aerobic treatment even if low effluent concentrations are demanded. The goal of this work is to optimize a MFC-based wastewater treatment process. A MFC mathematical model, which accounts for co-existence of methanogenic and anodophilic microbial populations, 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) co-existence of the two populations decreases reactor performance, and (iii) reactors connected in series always improves treatment efficiency.