Trifluoromethanesulfonic anhydride has been widely used in synthetic organic chemistry, not only for the conversion of various oxygen‐containing compounds to the triflates, but also for the electrophilic activation and further conversion of amides, sulfoxides, and phosphorus oxides. In recent years, the utilization of Tf2O as an activator for nitrogen‐containing heterocycles, nitriles and nitro groups has become a promising tool for the development of new valuable methods with considerable success. In addition, Tf2O has been used as an efficient radical trifluoromethylation and trifluoromethylthiolation reagent due to the contained SO2CF3 fragment, and significant progress has been made in this area. This review summarizes the recent progress in the applications of Tf2O in the above two aspects, and aims to illustrate the role and potential application of this reagent in organic synthesis.