Liquid chromatography/mass spectrometry (LC-MSⁿ) has been essential to a large number of quantitative analytical applications in drug research, and especially in the drug PK/PD research, due to its high sensitivity and high specificity.  But following the appearance of drugs with high activity and low dosage and the especial structural compounds, a number of limitations of LC-MSⁿ have been noted.  Derivatization changes the structure of drugs and therefore changes their physical and chemical properties, resulting in high ionization efficiency, low matrix effect and low disturbance by inorganic salts and endogenous compounds in LC-MSⁿ.  In this article, recent progress in the research of the chemical derivatization strategy with LC-MSⁿ is reviewed on breakthrough of some LC-MSⁿ limitations, in particular focusing on the applications involving some drugs in bio-matrices.