Autoimmune diseases include a diverse group of over 80 conditions. Sjögren's syndrome is the second most common autoimmune rheumatic disease, with an estimated prevalence in the United States of 2–4 million persons. There are prominent and consistent oral and dental findings in Sjögren's syndrome related to the autoimmune-mediated loss of normal salivary function. Additionally, nonoral clinical manifestations of Sjögren's syndrome include: dry eyes (with specific ocular surface changes termed keratoconjunctivitis sicca); other xeroses, such as dryness of the nose, throat, skin, and vagina; peripheral (and less frequently central) neuropathies; myalgias and arthralgias; thyroid disorders (particularly autoimmune thyroiditis); pulmonary disorders; renal disorders; and lymphoma. There is a significant (20- to 40-fold) increase in the incidence of malignant lymphoma, particularly in primary Sjögren's syndrome. Establishing the diagnosis of Sjögren's syndrome has been difficult in the light of its nonspecific symptoms (dry eyes and mouth), disagreement on diagnostic criteria, and a lack of both sensitive and specific laboratory markers. Many serum and salivary biomarkers for Sjögren's syndrome have been proposed although, to date, none has proven to be sufficiently specific for diagnostic purposes or has been well correlated with disease activity measures. Investigators have recently begun to apply modern genomic and proteomic approaches to identify candidate biomarkers in Sjögren's syndrome. The results of these investigations promise to provide a wealth of information on candidate biomarkers and possible etiopathological mechanisms underlying this disorder. Further, this information will improve clinical outcomes by fostering the design of new rational therapeutics and assisting in the monitoring of clinical disease.