Sample multiplexing using isobaric tagging techniques allows for up to 18 samples to be simultaneously compared using the TMTpro18 reagent set. This talk will showcase the history of sample multiplexing using isobaric tagging and specifically the TMT reagent storyline. In addition, the challenge of overcoming ratio distortion due to co-isolation and co-fragmentation will be described along with possible solutions. Moreover, the use of emerging targeted proteomics methods for sample multiplexing will be explored. Finally, to highlight the ability of 16plex sample multiplexing to exploit complex experimental designs, I will describe a large unpublished dataset from a collaboration between my lab, Dr. Joao Paulo’s lab and Jackson labs quantifying tissue-specific protein expression differences across eight fully-sequenced inbred founder mouse strains with five females and five males from each strain. Twelve different tissues were examined using 60 separate TMT16plex experiments. Sex-, tissue-, and strain-specific differences will be highlighted.