A method to use matrix-assisted laser desorption/ionization mass spectrometry MALDI-MS) for real time monitoring of organic reactions on polymeric supports used in solid-phase synthesis is described. The strategy utilizes a synthetic construct that allows for the rapid and convenient direct MALDI analysis of the attached substrates as well as their subsequent chemical cleavage as desired. We have used this strategy to monitor nucleophilic substitutions, palladium-catalyzed coupling reactions, and solid phase peptide synthesis reactions using both Boc- and Fmoc-based chemistries.