AIM: To summarize the collective in vitro, in vivo and clinical evidence of the involvement of the receptor activator of NF-κB ligand (RANKL)-osteoprotegerin (OPG) system, a system of two molecules controlling osteoclast differentiation and hard-tissue resorption, in pulpal and periapical pathophysiology. METHODOLOGY: A systematic search related to RANKL and/or OPG and pulp or periapical disease was conducted on Medline, Biosis, Cochrane, Embase and Web of Science databases using keywords and controlled vocabulary. No language restriction was applied. Two independent reviewers first screened titles and abstracts and then the full texts that were initially included. The reference lists of the identified publications were examined for additional titles. RESULTS: A total of 33 papers were identified. In vitro studies (N = 11) revealed that pulpal cells can be stimulated by various inflammatory agents to produce RANKL, whilst many studies did not consider the RANKL/OPG ratio. Animal studies (N = 9) mostly focused on the time course and development of periapical lesions in relation to the RANKL-OPG system. Levels of RANKL and OPG in the necrotizing pulp were not investigated. Human studies (N = 13) showed a steady-state expression of OPG in the odontoblast layer. Conflicting results have been reported regarding the role of RANKL in active apical periodontitis, again because the correlation of this molecule with its inhibitor (OPG) was often disregarded. CONCLUSIONS: There is relatively little information currently available that would highlight the specific role of RANKL and OPG in pulpal and periapical disease. OPG may play a protective role against internal resorption, whilst an increased periapical RANKL/OPG ratio might indicate bone resorption.