Plants serve as rich repositories of diverse chemical compounds collectively referred to as specialized metabolites (SMs). These compounds are of importance for adaptive processes, including interactions with various microbes both beneficial and harmful. Considering microbes as bioreactors, the chemical diversity undergoes dynamic changes when root-derived specialized metabolites (RSMs) and microbes encounter each other in the rhizosphere. Recent advancements in sequencing techniques and molecular biology tools have not only accelerated the elucidation of biosynthetic pathways of RSMs but also unveiled the significance of RSMs in plant-microbe interactions. In this review, we provide a comprehensive description of the effects of RSMs on microbe assembly in the rhizosphere and the influence of corresponding microbial changes on plant health, incorporating the most up-to-date information available. Additionally, we highlight open questions that remain for a deeper understanding of and harnessing the potential of RSM-microbe interactions to enhance plant adaptation to the environment. Finally, we propose a pipeline for investigating the intricate associations between root exometabolites and the rhizomicrobiome.