Abstract: Fluorinated compounds, which now make up 20%-25% of all marketed chemical drugs, are playing significant role and showing great potential in medicinal chemistry. Fluorine substitution is always utilized to change the physicochemical properties of the compounds to improve the ADME/T properties. In addition, fluorine substitution leads to improvement of the ligand binding affinity. With respect to molecular level, organofluorine can form various intermolecular interactions with the target proteins, e.g., hydrogen bond, halogen bond, C-F…π interaction, polar interaction and so on. These interactions display unique properties or nature due to the specificity of fluorine atom, which are at the center of attention. This paper reviews the related research background, followed by the research progress of hydrogen bond, halogen bond, C-F…π interaction, polar interaction and some other interactions involved organofluorine.