Increased awareness of the environmental and health concerns of consuming chemically synthesized products has led to a rising demand for natural products that are greener and more sustainable. Despite their importance, however, industrial-scale production of natural products has been challenging due to the low yield and high cost of the bioprocesses. To cope with this problem, systems metabolic engineering has been employed to efficiently produce natural products from renewable biomass. Here, we review the recent systems metabolic engineering strategies employed for enhanced production of value-added natural products, together with accompanying examples. Particular focus is set on systems-level engineering and cell physiology engineering strategies. Future perspectives are also discussed.