Bitterness is a major sensory attribute of several common foods and beverages rich in polyphenol compounds. These compounds are reported as very important for health as chemopreventive compounds, but they are also known to taste bitter. In this work, the activation of the human bitter taste receptors, TAS2Rs, by six polyphenol compounds was analyzed. The compounds chosen are present in a wide range of plant-derived foods and beverages, namely, red wine, beer, tea, and chocolate. Pentagalloylglucose (PGG) is a hydrolyzable tannin, (-)-epicatechin is a precursor of condensed tannins, procyanidin dimer B3 and trimer C2 belong to the condensed tannins, and malvidin-3-glucoside and cyanidin-3-glucoside are anthocyanins. The results show that the different compounds activate different combinations of the ~25 TAS2Rs. (-)-Epicatechin activated three receptors, TAS2R4, TAS2R5, and TAS2R39, whereas only two receptors, TAS2R5 and TAS2R39, responded to PGG. In contrast, malvidin-3-glucoside and procyanidin trimer stimulated only one receptor, TAS2R7 and TAS2R5, respectively. Notably, tannins are the first natural agonists found for TAS2R5 that display high potency only toward this receptor. The catechol and/or galloyl groups appear to be important structural determinants that mediate the interaction of these polyphenolic compounds with TAS2R5. Overall, the EC(50) values obtained for the different compounds vary 100-fold, with the lowest values for PGG and malvidin-3-glucoside compounds, suggesting that they could be significant polyphenols responsible for the bitterness of fruits, vegetables, and derived products even if they are present in very low concentrations.