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Taking the advantages of the chemical conversion of analytes through chemical reactions either in the solution or gas phase, very often an instrumental analytical problem can be addressed in a completely different way. This is at large due to the involvement of the chemical resolution in instrumental analysis. This review is focused specifically on contributions of chemical reactions to the development of novel instrumental analytical techniques in chromatography-mass spectrometry in the past two decades. It covers first the commercial instrumentations based on chemical reactions of analytes in the gas phase such as chemical ionization in gas chromatography- mass spectrometry (GC-MS), atmospheric pressure chemical ionization in liquid chromatography-mass spectrometry (LC-MS), proton- transfer reaction GC-MS for volatile organic compounds, and chemical reaction interface-mass spectrometry as a universal detector for GC, LC and size-exclusion chromatography (SEC) separation. Additionally, the recent development of a novel technique based on selective reactions of chemical noise ions with chosen neutral reagents for the reduction of chemical background noise in LC-MS trace analysis is also reviewed. The contribution of ion-molecule reactions to each instrumentation and their applications compared to other conventional techniques will be discussed.