Funding: Centro de Química Estrutural is a Research Unit funded by Fundação para a Ciência e Tecnologia through projects UIDB/00100/2020 and UIDP/00100/2020. Institute of Molecular Sciences is an Associate Laboratory funded by FCT through project LA/P/0056/2020. A.M. Matos thanks FCT, CQE, and Faculdade de Ciências da Universidade de Lisboa for her CEECInst Junior Researcher Contract, and FCT for funding through the Individual Call for Scientific Employment Stimulus (2022.07037.CEECIND). CBIOS—Universidade Lusófona’s Research Center for Biosciences & Health Technologies is a Research Unit funded by Fundação para a Ciência e Tecnologia through projects grants UIDB/04567/2020 and UIDP/04567/2020 to CBIOS. R.M. also thanks FCT and CBIOS for her CEECInst Assistant Researcher Contract (CEEC/04567/CBIOS/2020) and COFAC/ILIND—Cooperativa De Formação e Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021). The type 2 diabetes epidemic is real and hardly coming to an end in the upcoming years. The efforts of the scientific community to develop safer and more effective compounds for type 2 diabetes based on the structure of natural (poly)phenols are remarkable and have indeed proven worthwhile after the introduction of gliflozins in clinical practice. However, low-quality reports on the antidiabetic potential of plant-derived lipophilic (poly)phenols continue to pile up in the literature. Many of these compounds continue to be published as promising functional nutrients and antidiabetic pharmaceutical leads without consideration of their Pan-Assay Interference Compounds (PAINS) profile. This evidence-based opinion article conveys the authors' perspectives on the natural (poly)phenol artillery as a valuable and reliable source of bioactive compounds for diabetes. Ultimately, in light of the already established membrane-perturbing behavior of lipophilic (poly)phenols, together with the multiple benefits that may come with the introduction of a C-glucosyl moiety in bioactive compounds, we aim to raise awareness of the importance of contemplating the shift to (poly)phenol-carbohydrate combinations in the development of functional nutrients, as well as in the early stages of antidiabetic drug discovery. publishersversion published