Microbial fuel cells (MFCs) stand out as a potential eco-friendly technology to treat wastewater with the concomitant production of electricity, offering benefits regarding heavy metal removal. Innovations in this technology include the optimization of microbial consortia through artificial symbiosis, enhancing synergistic interactions for better bioelectrochemical processes and the development of biodegradable electrode materials that boost both performance and sustainability. The significance of anode–cathode configurations is also critical for optimizing energy output. Genetic modification and synthetic biology are considered to increase microbial metabolic capabilities and tailor microorganisms for removal of heavy metals, respectively. Promotion of electroactive biofilms is highlighted for its potential to increase electron transfer efficiencies as well. Adaptations of MFCs to various operational conditions and resistance to inhibitors are essential for robust performance in diverse scenarios. Additionally, in this chapter, the pretreatment of wastewater and optimization of operational parameters like pH, temperature, electrode material and microorganism selection are discussed to enhance MFC efficiency and longevity. Although advancements have been made over the years, the challenges of scaling up and integration remain significant, pointing out the necessity for designs that can be scaled up and robustly applied. This chapter also focuses on future research strategies emphasizing the integration of biological sciences, materials science and engineering approaches to address current limitations and expand MFC applications in real wastewater treatment scenarios.