The key to link intake of polyphenols to health benefits is the quantitative and kinetic assessment of their metabolites in circulation. Current analytical approaches have only provided limited quantitative coverage of the internal polyphenol metabolome, this in particular pertains to conjugated microbial catabolites. Current modelling approaches to describe the kinetic appearance of polyphenol metabolites into circulation mostly neglect the multi-compartment nature of polyphenol metabolism in the body. Furthermore, inter-individual variation is mostly neglected in current modelling approaches. These gaps hamper clear definition of the modulating effects of metabotypes and food matrix on the internal polyphenol metabolome.