Abstract: High performance chromatography coupled with high-resolution mass spectrometer (HPLC-HRMS) has been widely used to discover and identify drug metabolites due to its high sensitivity, rapidity and high mass accuracy. Drug metabolites can be rapidly detected and identified based on mass data (high resolution mass and multiple stage mass) and mass data processing strategy. This paper reviews the strategies and applications for the discovery and identification of drug metabolites using HPLC-HRMS after consulting related papers in recent years. These strategies, including extracted-ion chromatography (EIC), mass defect filter (MDF), isotope pattern filter (IPF), background subtraction (BS), product ion filter (PIF), mass spectral trees similarity filter (MTSF), SWATH and MS^E, were developed for the detection and identification of drug metabolites in complex biologic systems. Drug metabolites can be effectively detected and identified through the joint application of one or more strategies.