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Fibroblasts represent the most abundant population within the dental pulp. Although other cell types such as odontoblasts and stem cells have been extensively investigated, very little attention was given to the fibroblasts, which have major roles in regulating the pulp biology and function under normal and pathologic conditions. Indeed, although pulp fibroblasts control the pulp vascularization and innervation under physiological conditions, these cells synthesize growth factors that enhance dentin-pulp regeneration, vascularization, and innervation. Pulp fibroblasts also represent a unique cell population because they are the only non-hepatic and non-immune cell type capable of synthesizing all complement proteins leading to production of biologically active fragments such as C3a, C5a, and membrane attack complex, which play major roles in the pulp regeneration processes. C3a fragment is involved in inducing the proliferation of both stem cells and pulp fibroblasts. It is also involved in stem cell mobilization and pulp fibroblast recruitment. C5a guides nerve sprouting and stem cell recruitment. The membrane attack complex fixes on cariogenic bacteria walls, leading to their direct destruction. These data demonstrate the central role played by pulp fibroblasts in regulating the dentin-pulp tissue by directly destroying cariogenic bacteria and by releasing bioactive fragments involved in nerve sprouting and stem cell recruitment and pulp regeneration. Taken together, this shows that targeting pulp fibroblasts represents a realistic strategy to induce complete dentin-pulp regeneration.