The concept of “one gene, one target, one disease” has greatly impacted drug discovery methods. Effective medications now often target numerous targets, rather than just one. Network pharmacology, a multidisciplinary approach based on system biology and polypharmacology, proposes a new network mode of “multiple targets, multiple effects, complex diseases” that replaces “magic bullets” with “magic shotguns.” Chinese herbal medicine (CHM) is an important method in complementary and alternative medicine. Some of the tools used to execute Polypharmacological networks are Traditional herbal medicine (THM), Smart graph, Cytoscape, TCMSP, BATMAN-TCM, TCMID, and ETCM. Traditional medicine has always relied on natural ingredients as medicinal agents for several diseases. With the progress of genetics and bioinformatics, contemporary natural product discovery has transitioned to bottom-up tactics, which supplement traditional top-down procedures. This book chapter looks at the two primary approaches to natural product discovery: top-down and bottom-up. Top-down approaches start at the organism level and use systems-level perturbations to induce the production of novel natural products, whereas bottom-up approaches start with identifying a specific gene cluster of interest and then apply gene manipulation techniques to facilitate transcription, translation, and synthesis of the desired natural product. This book chapter also highlights the network toxicology, tools and databases used for network pharmacology, its applications, and limitations.