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Dental pulp regeneration after pulp necrosis in immature teeth represents a major departure from traditional endodontic therapy of these conditions. Preliminary clinical attempts have shown the feasibility of developing mineralized repair tissue, which may provide a clinically acceptable outcome. However, this outcome may not provide sufficient host response and root strength to ensure the longevity of the involved teeth. It is not clear if these preliminary suboptimal results are caused by the inability to fully disinfect the pulp space or the absence of a suitable progenitor cell/scaffold template together with adequate vascularity. Moreover, it is not known to what degree the root canal system needs to be disinfected in order for clinical success to be evident. This article describes the current clinical strategies and protocols for the optimal disinfection and preparation of the pulp space environment to promote periapical healing as well as soft and hard tissue development after an infectious process. Current and future strategies for disinfecting the pulp space with minimal disruption of the necessary biological factors from dentin, the progenitor cells in periapical vital tissues, and the vascularity are discussed. The potential for success of pulp regeneration after necrosis and infection would transform the practice of endodontics, even for mature teeth. This is a goal worth pursuing because it would achieve the restoration of normal host responses in the pulp space and the regeneration of destroyed dental tissues.