•We provide a comprehensive review of derivatization-based LC-MS studies.•We discuss the selection strategy for derivatization reagents.•We summarize the reaction mechanisms of representative derivatization reagents.•We describe the advancement of derivatization methods with advantages and prospects.•We summarize applications of derivatization in various research fields. Liquid chromatography-mass spectrometry (LC-MS) is one of the most prominent analytical techniques, due to its inherent selectivity and sensitivity. In LC-MS, chemical derivatizations are frequently used to enhance the MS ionization efficiency and selectivity, to facilitate structure elucidation, and to improve the chromatographic separation. In this review, we present an overview of derivatization-based LC-MS analysis. We summarize the reaction mechanisms of representative derivatization reagents and the selection strategy to guide and to stimulate future studies. Furthermore, we emphasize applications of derivatization in peptide and protein analysis, metabolite analysis, environmental analysis, pharmaceutical analysis, food-safety evaluation and MS imaging.