The clinical disorder Sjögren's syndrome and its putative histologic marker in salivary tissues, the lymphoepithelial lesion, have been and continue to be sources of confusion as well as the subjects of extensive immunologic and pathologic research. At the present time, Sjögren's syndrome is defined as a lymphocyte-mediated exocrinopathy but definition does little justice to the profound immunogenetic basis of the syndrome. This report presents a contemporary review of the lymphoepithelial lesion and the syndrome and presents a hypothesis of pathogenesis based on a graft vs host disease-like disorder. The hypothesis incorporates the immunogenetic, immunoregulatory, and neoplastic aspects of Sjögren's syndrome.