The impact of natural products on drug discovery pipelines keep kindling our interest in structurally unpredictable low-molecular-weight biomolecules as a promising source of pharmaceutical leads. Meanwhile, scientists are frequently frustrated by re-isolations of known compounds from new organism collections since countless natural products have been identified since Serturner’s characterization of morphine in 1806. To address this frustration, the affordability and chemical space expansion of minor new natural products become a great concern, and chemical synthesis has been performed to produce organism-originated complex molecules and natural product-like compounds with privileged scaffolds. To add more skills to the existing arsenal of searching for highly-valued new chemicals like drug leads, this talk will present the discovery and biosynthesis of bioactive secondary metabolites from symbionts, some of which are evidenced to be evolutionally advanced owing to their non-stop interaction with multicellular hosts such as plants, insects and fishes.