Liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESIMS/MS) is one of the most prominent analytical techniques owing to its inherent selectivity and sensitivity. In LC/ESI-MS/MS, chemical derivatization is frequently used to enhance the MS/MS detectability. The derivatization improves the separation and ionization efficiency. Moreover, the generated derivatives give particular product ions by CID (collision induced dissociation), which allow for the sensitive detection. In this review, we present an overview of the derivatization reagents which have been applied to LC/ESI-MS/MS, focusing on the applications involving small molecules in biomatrices.