Sjögren syndrome is a chronic systemic disease characterized by polyglandular tissue destruction leading to keratoconjunctivitis sicca (KCS) and xerostomia. Patients with primary Sjögren syndrome show evidence of KCS and xerostomia, whereas patients with secondary Sjögren syndrome suffer from KCS, xerostomia, and an autoimmune disease, most commonly rheumatoid arthritis. Certain factors cause autoimmune dysregulation leading to destruction of the acinar cells and ductal epithelia with subsequent dry eyes and dry mouth. Activated lymphocytes in patients with autoimmune diseases appear to have selective homing into the lacrimal and salivary glands leading to tissue damage. Understanding the factors involved in the immune dysregulation may improve our diagnostic and therapeutic approaches in Sjögren syndrome. Current therapeutic measures include means to increase secretion, relieve symptoms, and repair damage of the ocular surface.