Microbial fuel cell (MFC) technology has attracted a great amount of attention due to its potential for organic and inorganic waste treatment concomitant with power generation. It is thus seen as a clean energy alternative. Modifications and innovations have been conducted on standalone and hybrid/coupled MFC systems to improve the power output to meet the end goal, namely, commercialization and implementation into existing wastewater treatment plants. As the energy generated is inversely proportional to the size of the reactor, the stacking method has been proven to boost the power output from MFC. In recent years, stacked or scale-up MFCs have also been used as a power source to provide off-grid energy, as well as for in situ assessments. These scale-up studies, however, encountered various challenges, such as cell voltage reversal. This review paper explores recent scale-up studies, identifies trends and challenges, and provides a framework for current and future research. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.