Background/aims: The normal oral mucosa is usually tolerant to its special microenvironment. Epithelial integrity and a well-managed immune system are important in sustaining harmony. A close look at the role played by adaptive immunity during recurrent aphthous ulcerations may throw some light into the pathogenesis. Materials and Methods: In this report, we provide a concise review of oral epithelial barrier function and present data on the possible pathogenetic mechanism of aphthous ulceration using immunohistocemical signs of nuclear factor kappa beta pathway activation on fourteen cases of mucosal aphthous ulcerations. Results: We strongly support the hypothesis that oral aphthous ulcerations develop as a result of loss of epithelial barrier function and that nuclear factor kappa beta signaling pathway seems to be involved in this type of injury. Conclusion: Interventions that strengthen the mucosal barrier function or modulate inappropriate activation of nuclear factor kappa beta signaling pathway can be considered in the treatment of oral aphthous ulcerations.