<p>Oral and maxillofacial (OMF) tissue engineering has always been the subject of longstanding professional and academic debates. Despite rapidly evolving therapeutic approaches including reconstructive surgeries, tissue grafts, platelet-rich therapies, and mesenchymal stem cell–based treatments, there are remaining concerns regarding the therapeutic efficacy, safety profile, immunological compatibility, target-specificity, and ethical issues of such therapies. In addition to the multifactorial nature of OMF diseases, complex maxillofacial anatomy and neurovasculature further pinpoint the urgent need for breakthroughs in the era of OMF treatments. In recent years, exosomes have garnered immense popularity as the frontiers of regenerative medicine. Exosomes, natural nanovesicles secreted by a wide range of cells, act as nano messengers that harbor the rich molecular cargo received by their original cells and demonstrate important roles for diverse physiological and pathological intercellular communications. Among the different sources of exosomes, the oral cavity hosts a wide variety of mesenchymal stem cell–derived and salivary exosomes. Owing to the neural crest origin and multipotent differentiation, oral stem cell–derived exosomes hold great promise for OMF tissue engineering. Moreover, exosomes derived from pathological oral cavity cells and saliva samples provide diagnostic and prognostic signatures for different OMF diseases. This review highlights the cutting-edge diagnostic and therapeutic applications of oral cavity–derived exosomes in the field of OMF regeneration. Furthermore, we emphasize the existing challenges and constraints in exosome-based diagnostics and therapy, thus offering important perspectives for the future clinical application of exosomes derived from the oral cavity.</p> Graphical Abstract <p>Therapeutic potential of oral cavity–derived exosomes in oral and maxillofacial regeneration.</p> <p></p>