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Macrophages are major constituents of periapical granulomas. They have a central protective role in both innate immunity and adoptive, antigen-specific immune response. Macrophage activation may occur in periapical granulomas by cytokines produced by antigen-activated T-lymphocytes; by bacterial endotoxin, as part of the innate immunity; or by both these processes. Recent studies in athymic animals have shown that periapical granulomas may develop independently of T-lymphocytes. This observation reveals the major role that the activated macrophage may have in the formation of periapical lesions. Only a few of the macrophages in the periapical granuloma are activated. Current studies indicate that these activated cells are the source of the bone-resorbing cytokines in the periapical granuloma. Understanding the central role of the activated macrophage in the formation as well as the perpetuation of periapical lesions may lead to the development of new diagnostic and therapeutic tools in endodontics.