This talk will focus on our recent efforts in function and efficiency-driven total synthesis of medicinally important natural products. The target molecules include macrolides, alkaloids, and polycyclic diterpenoids. Novel and enabling synthetic strategies and methodologies toward these target molecules will be highlighted. Biological evaluation and target identification of the selected natural products and their analogs will be discussed as well. These biological endeavors have led us to the exciting territories of targeting the previously undruggable disease proteins via small-molecule inhibition and targeted protein degradation. Overall, this talk will emphasize how we use natural product total synthesis to achieve chemistry innovation and biological discovery.