Treatment of Sjögren's syndrome is almost entirely symptomatic. A lack of true understanding of the underlying immunological pathology of the disease prevents directed therapy. Interleukin-21 (IL-21) is elevated in the serum of patients with this disease and is expressed by the lymphocytes infiltrating the salivary glands. The known functions of IL-21 in facilitating differentiation, proliferation, and survival of both B and T cells mesh well with the findings in Sjögren's syndrome. Demonstration of IL-21 as a fundamental aspect of the pathophysiology of Sjögren's syndrome could lead to the development of anti-IL-21 therapy for this disease.