Microbial biomanufacturing is transforming the way chemicals, materials, pharmaceuticals, and natural products are produced by providing sustainable alternatives to conventional petrochemical synthesis and natural extraction. However, realizing economically viable bioprocesses requires microbial cell factories that achieve high titer, yield, productivity, robustness, and scalability—capabilities that cannot be attained through conventional metabolic engineering alone. To address these challenges, we developed systems metabolic engineering, an integrative framework that combines systems biology, metabolic engineering, synthetic biology, evolutionary engineering, and bioprocess engineering to enable the rational design and optimization of industrial microorganisms. In this lecture, I will present the principles and recent advances in systems metabolic engineering that have enabled the efficient production of a broad spectrum of industrial products, including bulk chemicals, polymers, fuels, proteins, and diverse natural products. Particular emphasis will be placed on our recent efforts to establish microbial platforms for the production of high-value natural products and their structurally diversified derivatives. These include the de novo reconstruction of complex biosynthetic pathways, engineering of precursor and cofactor metabolism, optimization of enzyme activities and pathway organization, dynamic metabolic regulation, and combinatorial biosynthesis for generating expanded chemical diversity. I will also demonstrate how computational approaches can be integrated with microbial engineering to construct large libraries of natural-product analogues and prioritize bioactive molecules for pharmaceutical applications, thereby accelerating both natural-product discovery and development. The lecture will further discuss how artificial intelligence is reshaping systems metabolic engineering by enhancing pathway discovery, enzyme engineering, and strain optimization. Collectively, these advances establish systems metabolic engineering as a foundational technology for next-generation biomanufacturing. By integrating biological design, computational intelligence, and scalable bioprocess engineering, systems metabolic engineering is expanding the accessible chemical space of biology and enabling sustainable production of chemicals, materials, pharmaceuticals, and natural products that will support the emerging global bioeconomy.