OBJECTIVE: We attempt to critically review regulatory mechanisms controlling the activity of effector cells and molecules contributing to protection-from-infection, host tissue injury and repair processes in apical periodontitis lesions. METHODS: Results of recent experimental and clinical observations made by our group and available in the scientific literature were reviewed. RESULTS: Protective and destructive immune-inflammatory reactions take place simultaneously in periapical lesions. However, the same “protective” reactions defending the periapical area from extensive infection may result in tissue injury. Recent results revealed new aspects of multiple and, in part, interrelated stimulatory and inhibitory effects, operative in apical periodontitis. Periapical inflammation is initiated by root canal infection in the majority of cases. In addition to microorganisms, dental materials and orthodontic tooth movement stimulate the expression of early inflammatory cytokines and chemokines by the cells of the pulp and of the periodontal ligament attracting leukocytes to the lesion site and stimulate their activities. Immigrating leukocytes produce further mediators amplifying the intensity of inflammation and resulting in tissue injury. Negative feed-back loops, at the cellular and molecular levels, inhibiting uncontrolled tissue damage and contributing to repair mechanisms are being set in motion parallel to the inflammatory reactions. The net balance of the networking regulatory processes is chronic apical periodontitis, a limited lesion in terms of both infection control and tissue injury, that can get completely healed after proper endodontic treatment. CONCLUSIONS: Development, progression and repair of periapical inflammatory lesions require the intricate interplay of virtually every subpopulation of inflammatory cells and mediators. Experimental models should be scrutinized before extrapolating observations to the periapical pathoses of human subjects. The work/publication is supported by the TÁMOP 4.2.1/B-09/1/KONV-2010-0007 project. The project is co-financed by the European Union and the European Social Fund.