The periodontium is an unusually complex tissue comprised of two hard (cementum and bone) and two soft (gingiva and periodontal ligament) tissues To date, restoration of damaged or diseased periodontal tissues has relied almost entirely on the use of implantation of structural substitutes, often with little or no reparative potential. Due to issues such as the variability in safety, clinical effectiveness and stability over time of these agents, their use for periodontal regeneration has been questioned. Advances in stem cell biology and regenerative medicine have presented opportunities for tissue engineering and gene–based approaches in periodontal therapy. These new approaches offer interesting alternatives to existing therapies for the repair and regeneration of the periodontium. Here, we review current understanding of stem cells, their potential application in regenerative periodontal therapy, and discuss the challenges of translating stem cell research into clinical practice