From the last few years, due to the inadequacies of, in practice, physiochemical methods, growing scientific awareness, increasing ecological/environmental concerns, and legal boundaries, many industries are currently pursuing enzyme‐based approaches for developing green chemistry technologies. Proteases, responsible for proteolysis, are vitally important for life and engaged with vast industrial applications as they are eco‐friendly in nature. According to the bioinformatics, protease constitutes approximately 2% of the total human genome, whereas extracellular protease is a highly exploitable enzyme in various industries due to its robust nature, and commercially available with the trade name of Savinase, subtilisin Carlsberg, and subtilisin BPN′. Genetic modifications and immobilization revealed a novel protease production strategy with superior catalytic efficacy and improved constancy toward pH or temperature. A vast literature exists on biological activities of protease but only a few reports are available on the nutritional effects and the physiochemical parameters for fermentative production of protease, which offers new possibilities and potentials to fulfill the industrial demands of enzymes. This article focuses on the updated tidings on nutritional effects, physiochemical parameters, biochemical aspects, and strain improvement methodologies for hyperproduction of protease. This article also addresses existing challenges and tentative solutions for successful utilization of protease for industrial applications. © 2016 American Institute of Chemical Engineers Environ Prog, 36: 511–522, 2017