A wide variety of stimuli can trigger activation of the transcription factor CREB (cAMP-responsive element binding protein), pointing toward a central role for CREB in the integration of various signaling inputs. No data are available on the expression and phosphorylation of CREB in mammalian teeth. Using immunohistochemical analysis of free-floating sections, we show here that CREB was strongly expressed and phosphorylated at Ser-133 within the nucleus of a subpopulation of adult human molar odontoblasts. Many dental pulp stromal cells and periodontal ligament fibroblasts expressed CREB and showed phosphorylation of CREB at Ser-133. In addition, cementoblasts displayed nuclear expression and phosphorylation of CREB at Ser-133. The epithelial rests of Malassez revealed strong nuclear expression of CREB, but phosphorylation at Ser-133 was variable. Our results provide the first evidence that the constitutively phosphorylated transcription factor CREB is involved in the biomineralization process of adult human molar odontoblasts and cementoblasts.