To address climate change by mitigating greenhouse gas emissions, there is a pressing need to develop technologies that can facilitate replacing crude oil with alternative, renewable feedstocks to manufacture fuels and chemicals. Precision fermentation has emerged as promising for the sustainable manufacturing of biofuels and bioproducts. Developments in metabolic engineering of microbial candidates have enabled the biological production of commercially significant chemicals including succinic acid (e.g., by Issatchenkia orientalis), 3-hydroxypropionic acid (3-HP; e.g., by Corynebacterium glutamicum), and triacetic acid lactone (TAL; e.g., by Yarrowia lipolytica), among others. We leveraged BioSTEAM—an open-source platform—to design, simulate, and evaluate under uncertainty (via techno-economic analysis, TEA, and life cycle assessment, LCA) biorefineries producing these chemicals by fermentation of substrates obtained from renewable feedstocks including sugarcane and corn stover. Further, we simulated and evaluated entire theoretical fermentation performance landscapes (e.g., formed by all potential combinations of fermentation yield, titer, and productivity) in each of these biorefineries, revealing fermentation development pathways to achieve system-wide sustainability targets. This presentation will showcase how agile and robust system analyses can elucidate key drivers of system cost and environmental impacts across technological landscapes, chart roadmaps to navigate the opportunity space for precision fermentation, and prioritize research, development, and deployment needs for financial viability and environmental benefits.