The incorporation of covalent fluorine has been widely used as an effective strategy in medicinal chemistry for drug discovery. The introduction of fluorine into a molecule can significantly influence conformation, lipophilicity, pKa, metabolism, and pharmacokinetic properties. In 1955, the first fluorinated drug fludrocortisone has been approved in the market for the treatment of the adrenogenital syndrome, postural hypotension, and adrenal insufficiency. Since then, 218 small-molecule drugs with at least one fluorine atom have been launched by U.S. FDA by the end of 2018. Therefore, this chapter is expected to summarize the fluorine-containing natural products in clinical development to the medicinal chemistry community.