The inclusion of preliminary chemical labeling (derivatization) in the analysis process by such powerful and widespread methods as electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is a popular and widely used methodological approach. This is due to the need to remove some fundamental limitations inherent in these powerful analytic methods. Although a number of special reviews has been published discussing the utilization of derivatization approaches, the purpose of the present critical review is to comprehensively summarize, characterize and evaluate most of the previously developed and practically applied, as well as recently proposed representative derivatization reagents for ESI-MS and MALDI-MS platforms in their mostly sensitive positive ion mode and frequently hyphenated with separation techniques. The review is focused on the use of preliminary chemical labeling to facilitate the detection, identification, structure elucidation, quantification, profiling or MS imaging of compounds within complex matrices. Two main derivatization approaches, namely the introduction of permanent charge-fixed or highly proton affinitive residues into analytes are critically evaluated. In situ charge-generation, charge-switch and charge-transfer derivatizations are considered separately. The potential of using reactive matrices in MALDI-MS and chemical labeling in MS-based omics sciences is given.