The regeneration of periodontal tissue poses a significant challenge to biomaterial scientists, tissue engineers and periodontal clinicians. Recent advances in this field have shifted the focus from the attempt to recreate tissue replacements/constructs ex vivo to the development of biofunctionalized biomaterials that incorporate and release regulatory signals in a precise and near-physiological fashion to achieve in situ regeneration. The molecular and physical information coded within the biomaterials define a local biochemical and mechanical niche with complex and dynamic regulation that establishes key interactions with host endogenous cells and, hence, may help to unlock latent regenerative pathways in the body by instructing cell homing and regulating cell proliferation/differentiation. In the future, these innovative principles and biomaterial devices promise to have a profound impact on periodontal reconstructive therapy and are also likely to reconcile the clinical and commercial pressures on other tissue engineering endeavors. (c) 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2012