Introduction: Quantitative proteomics using mass spectrometry is performed via label-free or label-based approaches. Labeling strategies rely on the incorporation of stable heavy isotopes by metabolic, enzymatic, or chemical routes. Isobaric labeling uses chemical labels of identical masses but of different fragmentation behaviors to allow the relative quantitative comparison of peptide/protein abundances between biological samples. Areas covered: We have carried out a systematic review on the use of isobaric mass tags in proteomic research since their inception in 2003. We focused on their quantitative performances, their multiplexing evolution, as well as their broad use for relative quantification of proteins in pre-clinical models and clinical studies. Current limitations, primarily linked to the quantitative ratio distortion, as well as state-of-the-art and emerging solutions to improve their quantitative readouts are discussed. Expert opinion: The isobaric mass tag technology offers a unique opportunity to compare multiple protein samples simultaneously, allowing higher sample throughput and internal relative quantification for improved trueness and precision. Large studies can be performed when shared reference samples are introduced in multiple experiments. The technology is well suited for proteome profiling in the context of proteomic discovery studies.