Conventional energy sources are limited and non-renewable and their consumption contributes to greenhouse gas emissions. The world is in need of advanced biorefineries to meet ever growing energy demands associated with population growth and economic development. An advanced biorefinery should use renewable and sustainable (both in quality and quantity) feedstock that gives rise to higher energy gains with minimumnon-renewable energy and resource consumption. Development of advanced biorefineries is currently encircled by two major issues. The first issue is to ensure adequate biofuel feedstock supplies while the second issue is to develop resource-efficient technologies for the feedstock conversion to maximize energy and economic and environmental benefits. While microalgae, microbial derived oils, and agricultural biomass and other energy crops show great potential for meeting current energy demands in a sustainable manner, process intensification and associated synergism can improve the resource utilization efficiency. Synergism of process intensification tools is important to increase energy efficiency, reduce chemical utilization and associated environmental impacts, and finally process economics. Among the many process intensification methods, this commentary provides a perspective on the essential role of MWs and US and their synergy in biofuel production. Individual, sequential, and simultaneous applications of MWs and US irradiations can be utilized for process intensification of various biofuels production and selective recovery of high value bioproducts. Process related barriers, namely mass and heat transfer limitations, can be eliminated by this synergism while improving the reaction efficiency and overall process economics significantly. In this article, a brief review focused on recent developments in MW and US mediated process intensification for biofuel synthesis and associated issues in their synergism followed by a discussion on current challenges and future prospective is presented.