Phytochemicals containing heteroatoms (N, O, S, and halogens) often have biological activities that are beneficial to humans. Although targeted profiling methods for such phytochemicals are expected to contribute to rapid chemical assignments, thus making phytochemical genomics and crop breeding much more efficient, there are few profiling methods for the metabolites. Here, as an ultrahigh performance approach, we propose a practical profiling method for S-containing metabolites (S-omics) using onions (<i>Allium cepa</i>) as a representative species and <sup>12</sup>C- and <sup>13</sup>C-based mass spectrometry (MS) and tandem mass spectrometry (MS/MS) analyses by liquid chromatography–Fourier transform ion cyclotron resonance-mass spectrometry (LC–FTICR-MS). Use of the ultrahigh quality data from FTICR-MS enabled simplifying the previous methods to determine specific elemental compositions. MS analysis with a resolution of >250 000 full width at half-maximum and a mass accuracy of <1 ppm can distinguish S-containing monoisotopic ions from other ions on the basis of the natural abundance of <sup>32</sup>S and <sup>34</sup>S and the mass differences among the S isotopes. Comprehensive peak picking using the theoretical mass difference (1.995 79 Da) between <sup>32</sup>S-containing monoisotopic ions and their <sup>34</sup>S-substituted counterparts led to the assignment of 67 S-containing monoisotopic ions from the <sup>12</sup>C-based MS spectra, which contained 4693 chromatographic ions. The unambiguous elemental composition of 22 ions was identified through comparative analysis of the <sup>12</sup>C- and <sup>13</sup>C-based MS spectra. Finally, of these, six ions were found to be derived from S-alk(en)ylcysteine sulfoxides and glutathione derivatives. This S-atom-driven approach afforded an efficient chemical assignment of S-containing metabolites, suggesting its potential application for screening not only S but also other heteroatom-containing metabolites in MS-based metabolomics.