Medicinal plants have been an inspiration source for developing new chemical entities, providing diverse chemical structures and modes of action for medicinal chemistry strategies. Modern medicinal chemistry approaches promote functional group changes to improve NCE’s biological activity. Incorporating the trifluoromethyl (-CF3) group into organic compounds is crucial in modern drug design. It may affect the compound's lipophilicity, solubility, stability, molecular conformation, and pKa, changes that may lead to the discovery of new medicines to treat diseases of our times. For this reason, this chemical transformation is currently a hot topic in the organic chemistry field. Chemists are competing to develop better methods to carry out this transformation efficiently, less hazardously, and cost-effectively. The high number of annual scientific publications on trifluoromethylation evidences the competition. This review profiles 21 trifluoromethylated New Chemical Entities (NCE) selected in December 2020 from the GlobalData database, mainly in late stages of clinical trials (Phase II and III) or already in the commercial phase, containing one or two -CF3 groups in para or meta positions of benzene, or a pyridine ring. Synthetic approaches, therapeutic applications, and manufacturing industrial challenges are provided.