Despite several limitations of untargeted approaches, HRMS can successfully be utilized for investigating the exposome, notably polyphenols and their metabolites in human samples besides many other exogenous and endogenous small molecules. For polyphenols, although HRMS has shown to have lower sensitivity for most of them, the differences are still in the range where HRMS is able to detect -and better characterize -the vast majority of polyphenols. Due to their higher naturally occurring concentration, e.g. concentrations ranging from 0.01 µM to over 1000 µM in human urine , and the more in-depth knowledge about these molecules compared to many other xenobiotics , HRMS can readily be used instead of LRMS for qualitative and semi-quantitative analysis of polyphenols with a great gain of information. Though targeted LRMS methods are still desired for benchmarking, HRMS has the advantage that it allows to study the exposome agnostically. Currently, polyphenols are frequently under-investigated in human matrices, but workflows such as the one presented here would allow seeing both positive and negative effects of these xenobiotics. For example, this workflow can be applied to investigate toxicological and pharmacological mixture effects of polyphenols with other xenobiotics, such as decreasing the potency of potentially harmful xenobiotics or interfering with drug treatment . Therefore, the authors strongly recommend the use of HRMS in complement to LRMS in the future investigation of effects from polyphenols and other xenobiotics on human nutritional and health studies.