The role of apoptosis in exocrine gland destruction associated with Sjögren's Syndrome is not well understood but there is increasing evidence that this is the mechanism of pathogenesis. In the following studies, using TUNEL assays, detection of activated caspase enzymes and detection and quantification of genes known to be involved in the apoptotic pathways, a mechanism of salivary pathogenesis in Sjögren's Syndrome is postulated and supporting evidence provided. The presence of the autoantigen, cleaved α-fodrin, has been demonstrated in human saliva and in diseased salivary gland. This may be a marker of disease within a specific sub-group of Sjögren's patients which paves the way to future translational research. Another important result is the co-localization of cleaved α-fodrin at the apoptotic site contiguous with DNA fragmentation, Caspase-3 and PARP in diseased tissues. Furthermore, unique cell morphology resulting from apoptosis of salivary cells but driven by activation of a specific pathway is another discovery. The regulation of, and the definitive pathway to apoptosis, is less well understood. To elucidate these pathways, interactions between nuclear transcription factor kappa B (NF-κB) thought to be a major regulator, and steroids such as glucocorticoids used in therapy, were completed in vitro. These studies also showed gene transfection of HSG cells by the super-repressor inhibitor of NF-κB (1uBaM) can increase apoptosis. The glucocorticoid studies indicated glucocorticoids may cause apoptosis and demonstrated the complexity of the system. Estrogens were also studied since Sjögren's Syndrome is predominantly a disease of post-menopausal women with estrogen deficiency. The results from the estrogen studies showed that estrogen can prevent apoptosis in vitro. The combined results suggest that the in vitro model may be useful to explore disease progression and the therapeutic value of drugs targeting salivary gland destruction.