The ability to precisely control activities of engineered designer cells provides a novel strategy for modern precision medicine. Dynamically adjustable gene- and cell-based precision therapies are recognized as next generation medicines. However, the translation of these controllable therapeutics into clinical practice is severely hampered by the lack of safe and highly specific genetic switches controlled by triggers that are nontoxic and side-effect free. Recently, natural products derived from plants have been extensively explored as trigger molecules to control genetic switches and synthetic gene networks for multiple applications. These controlled genetic switches could be further introduced into mammalian cells to obtain synthetic designer cells for adjustable and fine tunable cell-based precision therapy. In this review, we introduce various available natural molecules that were engineered to control genetic switches for controllable transgene expression, complex logic computation, and therapeutic drug delivery to achieve precision therapy. We also discuss current challenges and prospects in translating these natural molecule-controlled genetic switches developed for biomedical applications from the laboratory to the clinic.