Tandem mass spectrometry (MS/MS) is a powerful analytical tool that is used extensively for the characterization of complex mixtures in many fields, such as proteomics, petroleomics, and drug discovery. Currently, the most commonly used MS/MS technique to obtain structural information for ionized and isolated mixture components is collision-activated dissociation (CAD). In these experiments, the analyte ions are accelerated and allowed to collide with an inert gas, such as helium. Upon the collisions, part of the kinetic energy of the ions is converted into their internal energy, resulting in fragmentation. This approach is limited by the fact that isomeric ions often generate identical fragmentation patterns, making identification via CAD mass spectra unreliable. To address this issue, a MS/MS approach based on diagnostic, reliable and predictable gas-phase ion-molecule reactions has been developed. This approach can be used to identify specific functional groups or their combinations in separated and ionized mixture components to thereby facilitate the differentiation of isomeric ions, usually without the need for reference compounds.