The development of novel analytical methods to detect and identify chemical warfare agents (CWAs), their degradation products, metabolites, and precursors is of high importance as terrorist groups and radical regimes use or plan to use chemical weapons against civilians or military targets. Gas chromatography (GC) and liquid chromatography (LC), usually hyphenated with mass spectrometry (MS), are the major techniques used to detect and identify chemicals of concern according to the chemical convention. In this mini‐review, we describe the present state of research on the derivatization and modification of CWAs and related compounds for LC‐MS and atmospheric pressure ionization (API)‐based analysis reported in the open literature during the last 15 years. The more polar, reactive, or highly volatile agents are derivatized to expedite chromatography and to impart properties valuable for sensitive detection and identification by MS. In this article, we focus on trace analysis of CWAs, mostly G‐type nerve agents, blister agents (sulfur mustard (HD)), and the most famous blood agent, cyanide. Analytical applications are mainly in environmental matrices but also in biomedical matrices that support the investigation of CWAs use and monitoring of possible exposure to CWAs.