Microbial fuel cells (MFCs) have been conceived and intensively studied as a promising technology to achieve sustainable wastewater treatment. However, doubts and debates arose in recent years regarding the technical and economic viability of this technology on a larger scale and in a real-world applications. Hence, it is time to think about and examine how to recalibrate this technology's role in a future paradigm of sustainable wastewater treatment. In the past years, many good ideas/approaches have been proposed and investigated for MFC application, but information is scattered. Various review papers were published on MFC configuration, substrates, electrode materials, separators and microbiology but there is lack of critical thinking and systematic analysis of MFC application niche in wastewater treatment. To systematically formulate a strategy of (potentially) practical MFC application and provide information to guide MFC development, this perspective has critically examined and discussed the problems and challenges for developing MFC technology, and identified a possible application niche whereby MFCs can be rationally incorporated into the treatment process. We propose integration of MFCs with other treatment technologies to form an MFC-centered treatment scheme based on thoroughly analyzing the challenges and opportunities, and discuss future efforts to be made for realizing sustainable wastewater treatment.