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Increasing attention has been focused on the study of protein–metabolite interactions (PMI), which play a key role in regulating protein functions and directing an orchestra of cellular processes. The investigation of PMIs is complicated by the fact that many such interactions are extremely short-lived, which requires very high resolution in order to detect them. As in the case of protein–protein interactions, protein–metabolite interactions are still not clearly defined. Existing assays for detecting protein–metabolite interactions have an additional limitation in the form of a limited capacity to identify interacting metabolites. Thus, although recent advances in mass spectrometry allow the routine identification and quantification of thousands of proteins and metabolites today, they still need to be improved to provide a complete inventory of biological molecules, as well as all interactions between them. Multiomic studies aimed at deciphering the implementation of genetic information often end with the analysis of changes in metabolic pathways, as they constitute one of the most informative phenotypic layers. In this approach, the quantity and quality of knowledge about PMIs become vital to establishing the full scope of crosstalk between the proteome and the metabolome in a biological object of interest. In this review, we analyze the current state of investigation into the detection and annotation of protein–metabolite interactions, describe the recent progress in developing associated research methods, and attempt to deconstruct the very term "interaction" to advance the field of interactomics further. [ABSTRACT FROM AUTHOR]