Different factors and pathways are involved in the regeneration of the tooth-supporting structures based on the fact that hard connective tissue (bone/cementum) and soft connective tissue (periodontal ligament) have to be restored. Several approaches have been taken to regenerate periodontal tissues. Among these, it has been shown that the incorporation of biologic mediators can specifically stimulate and coordinate regenerative processes. Various procedures have focused on the use of biologic mediators and include the application of: i) a single factor, ii) a cocktail of factors, iii) cell-based therapy, and iv) tissue engineering principles. The use of single factors shows variation in regenerating tooth-supporting structures depending on the applied factor. The application of a combination of factors, either being a combination of current single products, or an existing product containing a combination of proteins, appears to be the most promising approach presently to stimulate both the soft and hard connective tissues. The biologic factors are generally dissolved in a liquid and must be combined with a carrier. In some cases, the carrier is not space making and the factor plus carrier must be applied with a space-maintaining device. Cell-based therapies open the door towards the use of “smart” technologies for the regeneration of the periodontium. However, a review of the literature with respect to tissue engineering where three components (biologic factor, carrier, cells) are used for regenerating tissue revealed few published papers for the oral cavity. In conclusion, the periodontium is a complex heterogeneous tissue made up of both soft and hard connective tissues. While current therapeutic efforts have focused on various approaches to stimulate periodontal regeneration, it is clear that there is a need for further developments and consequently, significant improvements in periodontal regenerative therapy.