AbstractPlant-microbe interactions dynamically affect plant growth, health, and development. The mechanisms underpinning these associations are—to a large extent—mediated by specialized host-derived secondary metabolites. Flavonoids are one of the most studied classes of such metabolites, regulating both plant development and the interaction with commensal microbes. Here, we provide a comprehensive review of the multiple roles of flavonoids in mediating plant-microbe interactions. First, we briefly summarize the general aspects of flavonoid synthesis, transport, and exudation in plants. Then, we review the importance of flavonoids regulating plant-microbe interactions and dynamically influencing the overall community assembly of plant-root microbiomes. Last, we highlight potential knowledge gaps in our understanding of how flavonoids determine the interactions between plants and commensal microbes. Collectively, we advocate the importance of advancing research in this area toward innovative strategies to effectively manipulate plant-microbiome composition, in this case, via flavonoid production and exudation in plant roots.