Analyte derivatization has played an important role in analysis using combined gas chromatography−mass spectrometry (GC/MS). In GC/MS, derivatization is performed to enhance the volatility of the analyte, to alter its ionization characteristics, or to influence its fragmentation behavior. In combined liquid chromatography−MS (LC−MS), however, where soft ionization techniques like electrospray (ESI) and atmospheric pressure chemical ionization (APCI) are applied, derivatization is generally not needed and avoided as much as possible. In LC−MS, derivatization is primarily used to improve ionization characteristics, especially for analytes that are not (efficiently) ionized by ESI or APCI such as aldehydes, sugars, and steroids. Derivatization strategies are then directed at the incorporation of a group with a permanent charge (cationic groups for positive-ion mode and strong acidic functionalities for negative-ion mode) or other groups that enhance ionization (secondary or tertiary amine for positive-ion mode or aromatic nitro groups in negative-ion mode). In addition, derivatization may be directed at improving the fragmentation characteristics in tandem MS (MS/MS).