Abstract: In recent years, the research of transdermal drug delivery systems (TDDS) represented by patches and gel plasters is in the ascendant. The interactions between drugs, pressure-sensitive adhesives, permeation enhancers and skin components, including hydrogen bonds, ionic interactions, dipole-dipole interactions, etc., play a key role in regulating the release and penetration of drugs in transdermal patches, thus affecting the efficiency of transdermal absorption of drugs. Infrared spectroscopy, molecular simulations or molecular docking, differential scanning calorimetry, Raman spectroscopy, nuclear magnetic resonance and other methods have been widely used to characterize multiple intermolecular interactions in patches. The aim of this review is to summary the molecular mechanisms of drug release from patches and transdermal permeation processes, provide useful theoretical guidance for the design and research of novel transdermal drug delivery systems.