Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry is useful for probing biomolecules heavier than 600 daltons, but it struggles to analyze small molecules. Now, researchers have discovered that simply deuterating the MALDI matrix allows them to identify previously hidden small molecules, including neurotransmitters and pharmaceuticals (Anal. Chem., DOI: 10.1021/ac301498m). In MALDI, clusters of matrix molecules often mask the signal of small molecules. Mohammadreza Shariatgorji, a postdoctoral researcher in Per E. Andrén’s medical mass spectrometry lab at Uppsala University, in Sweden, decided to alter the matrix signals slightly to uncover the signals of small molecules known to be hidden by certain matrix clusters. He and his colleagues replaced four aromatic hydrogens with deuterium in a standard matrix material, α-cyano-4-hydroxycinnamic acid (CHCA). The isotopes shifted the matrix peaks by 4, 8, or 12 Da for CHCA and for clusters of two or three CHCA molecules, respectively. To demonstrate the technique, Shariatgorji and his colleagues used it on rat tissue samples to identify three small molecules: a natural product, berberine; a synthetic drug, amiloride; and a neurotransmitter, acetylcholine.