Abstract: Bioisosterism is one of the most common strategies in drug structure optimization. With the development of medicinal and organic chemistry, more and more classic and non-classical bioisosteres are used in the design of novel drugs. In recent years, fluorinated groups as a bioisostere have been paid more and more attention by pharmaceutical chemists. This paper briefly reviews the physicochemical properties, chemical preparation methods of difluoromethyl (CF₂H) group, and its application in drug design to provide references for drug discovery researchers.