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• Efforts to enhance PMFC performance are reviewed. • Both exciting advancements and current limitations are discussed. • An innovative strategy of multi-scale simultaneous optimization is proposed. Paper-based microfluidic fuel cell (PMFC) has attracted great attention in the microfluidic fuel cell field in recent years. It utilizes the spontaneous capillary flow of reactant solutions in paper-based porous substrate to achieve passive transportations of fuel and oxidant, solving the fluid driving issue encountered in traditional microfluidic fuel cells and thus having broad application prospects in medical detection, wearable devices, micro sensors, environmental monitoring, and many other fields. However, the commercialization of this technology is impeded by the low output performance caused by the limited mass and energy transfer in PMFCs. To enhance the mass and energy transfer in PMFCs, numerous research studies have been conducted via experimental optimization of the cell materials and structures. Numerical analyses focusing on the structure–activity relationship of PMFCs were also performed recently. To provide a comprehensive and thorough review about the efforts devoted to improving performance of PMFC, research papers relevant to PMFC since its invention in 2014 have been extracted in this work and significant works were filtered to highlight the exciting advancements. The experimental studies were classified and discussed based on the key components involved in the PMFC system, followed by a critical review of the limited computational models. Potential directions for future research were also provided, aimed at overcoming the current technological challenges in PMFCs. Importantly, an innovative strategy of multi-scale simultaneous optimization of the cell properties is proposed considering the typical multi-scale feature of the PMFC system, which could inspire the designing of advanced cell materials with optimal multi-scale structures for applications of PMFCs. [ABSTRACT FROM AUTHOR]