Primary Sjögren's syndrome (pSS) is a systemic multiorgan autoimmune disease that runs a chronic progressive course. The recently developed treat-to-target paradigm involves identifying and targeting the molecular mechanisms that underlie disease manifestations in individual patients. This review discusses the immunopathology of pSS and the treatment approaches currently under investigation. To date, only symptomatic treatments are available for pSS, and only a few of the potential new treatment strategies have been evaluated. Among them, B-cell depletion is the most extensively investigated, although the data remain insufficient to support use in everyday practice. Specific patient subgroups likely to benefit from B-cell depletion may be identified in the future. Improved knowledge about the pathophysiology of pSS, the development of validated endpoints for evaluating treatment effects, and the currently unmet treatment needs of patients with pSS are now strong incentives for pharmaceutical firms to embark on randomized controlled trials.