Primary Sjögren's syndrome (SS) is a systemic autoimmune disease that is characterized by keratoconjunctivitis sicca and xerostomia resulting from lymphocytic infiltrates of the lacrimal and salivary glands. The criteria for the diagnosis of SS continue to be controversial, leading to confusion in the clinical and research literature. It is important to distinguish SS (an idiopathic autoimmune process) from other processes, including hepatitis C infection, autonomic neuropathy, and drug side effects, that can result in sicca symptoms. Recent studies on the pathogenesis of SS in humans and in animal models examine the clonality of the T cell infiltrates, cytokine production by lymphocytes and glandular epithelial cells, neuroendocrine and hormonal factors that affect glandular secretion, and the fine structure of antigens recognized by T and B cells. Studies of SS have allowed comparison of lymphocytes in blood and in the glandular tissue lesions; important differences in the gland microenvironment play an important role in the initiation and perpetuation of the autoimmune process. For example, apoptotic death depends on the balance of Fas, Fas ligand, nuclear factors (eg, bcl-2, bax, and myc), cytokines, neuropeptides, and cell membrane interactions with extracellular matrix. Although increased rates of apoptosis may be present in the blood T cells of SS patients, some glandular T cells are resistant to apoptosis. Recent advances have led to improved understanding of signal transduction in response to cytokines and hormones that play a role in the local and systemic manifestations of SS. New approaches to therapy are designed to improve the qualitative properties of corneal epithelial surface, as well as increase tear volume.