Oral and dental diseases are major public health problems worldwide, with a profound effect on quality of life. Current treatment modalities are based on non-biological artificial substitutes, such as dental fillings, fixed and removable partial dentures supported by teeth and/or implants, complete dentures etc. These substitutes have several disadvantages, including uncomfortable sensation, insufficient biocompatibility, damage to the surrounding tissues and unpredictable long-term therapeutic efficacy. This provides exemplary justification for identifying regeneration of oral/dental tissues as the “ultimate goal” of current tissue engineering strategies in regenerative dentistry. The discovery and characterization of stem cells (SCs) from various oral sources, such as the dental pulp, periodontal ligament, dental follicle, apical papilla, oral mucosa, orofacial bones, salivary glands and other together with the cutting edge research of recent years in understanding their biology have enhanced our knowledge of the complex role of SCs in developmental/repair processes. The application of this knowledge in translational studies has been a decisive milestone in bringing these technologies closer to clinical application. Amazing technological advances, such as development of customized biomimetic scaffolds, fine tuning of the stem cell niche microenvironent by means of bioreactors and single-cell analysis possibilities by means of microfluidics have provided valuable tools in translating scientific advances into clinical settings. Finally, establishment of Good Manufacturing Practice-GMP protocols according to European regulations and establishment of clinical-grade, xeno-free stem cell lines have facilitated feasibility and “proof-of-concept” clinical trials on the application of oral SCs in orofacial or other tissue regeneration. Most recently the potential to use the plethora of secreted throphic and immunomodulatory cytokines produced by SCs (known as secretome), as a therapeutic module instead of the cells has been proposed as a safer and effective alternative to SC transplantation highlighting the dilemma between stem cell vs. secretome therapy? This lecture will provide an overview of the biological properties of oral SCs, analyzing current research trends and critical milestones towards clinical application.