Background <p>Sjögren’s disease (SjD) is a clinically and biologically heterogeneous autoimmune disease with a wide range of glandular and systemic manifestations. Although significant progress has been made in elucidating its pathogenesis, current management remains predominantly symptomatic, and disease-modifying therapies are still lacking. The substantial heterogeneity of SjD poses major challenges for clinical trial design, treatment stratification, and the development of evidence-based guidelines.</p> Objective <p>This review summarizes recent advances in clinical and molecular endotyping of SjD and explores how these insights can inform the development of precision treat-to-target (T2T) strategies tailored to specific patient subgroups.</p> Content <p>We review the evolving landscape of SjD stratification, encompassing symptom-based clinical phenotypes, immunologic and transcriptomic endotypes, and cross-disease immune signatures. We highlight how distinct endotypes are associated with differential therapeutic responses, guiding the application of B cell-targeted therapies, interferon (IFN) pathway inhibitors, immune regulatory interventions, and metabolic modulators. The potential of dynamic monitoring approaches—including composite clinical endpoints, multi-omics biomarkers, and artificial intelligence-assisted stratification—is also discussed as a foundation for implementing precision T2T strategies in SjD. Finally, key challenges and future directions for clinical translation are addressed.</p> Conclusion <p>Precision T2T strategies, grounded in comprehensive clinical and molecular stratification, have the potential to improve individualized management of SjD. Future research should focus on validating dynamic monitoring tools and optimizing biomarker-guided treatment pathways to advance personalized care in this complex disease.</p>