Plant natural products (PNPs) hold significant pharmaceutical importance. The sessile nature of plants has led to the evolution of chemical defense mechanisms over millions of years to combat environmental challenges, making it a crucial and essential defense weapon. Despite their importance, the abundance of these bioactive molecules in plants is typically low, and conventional methods are time-consuming for enhancing production. Moreover, there is a pressing need for novel drug leads, exemplified by the shortage of antibiotics and anticancer drugs. Understanding how plants respond to stress and regulate metabolism to produce these molecules presents an opportunity to explore new avenues for discovering compounds that are typically under the detection limit or not naturally produced. Additionally, this knowledge can contribute to the advancement of plant engineering, enabling the development of new chassis for the biomanufacturing of these valuable molecules. In this perspective, we explore the intricate regulation of PNP biosynthesis in plants, and discuss the biotechnology strategies that have been and can be utilized for the discovery and production enhancement of PNPs in plants.