Sjogren's syndrome (SS) is an autoimmune epithelitis characterized by focal lymphocytic infiltration against self-antigens leading to progressive glandular dysfunction, which can develop to multisystem manifestation. The classification criteria for SS emphasizes glandular lymphocyte infiltrates and anti-SSA/SSB seropositivity, which is usually manifested in advanced patients. Therapeutically, apart from symptomatic treatment, treatment of SS is based on glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs with global immunosuppression, but the efficacy of biologic or targeted synthetic therapies is still sparse. Currently, emerging studies focus on autoantigen-specific immunotherapies to treat autoimmune disorders by directly eliminating autoreactive cell subsets and inducing tolerance by increasing the autoreactive regulatory lymphocytes. Herein, we summarize the current state of research on the autoantigen-specific approaches for detecting autoreactive lymphocytes and outline the current autoantigen-specific immunotherapies in other autoimmune disorders and their attempts in treatment of SS. Last, we discuss the potential value of focusing on autoantigen-specific lymphocytes in the early diagnosis, monitoring, and targeted treatment of SS. Potential strategies for targeting autoreactive lymphocytes need to be confirmed in SS.