Primary Sjogrens syndrome (pSS) is a common autoimmune disease which can lead to considerable complications and diminished quality of life. Recent insights into disease mechanisms and the advent of biological agents have provided new options for the treatment of pSS. In particular, B cell targeted intervention has shown promising results. In this review, we focus on emerging treatment strategies and therapeutic targets beyond B cells. Interference with proinflammatory cytokines and mechanisms that link innate and adaptive immunity offers new options in the treatment of pSS. Approaches directed against interleukin (IL)-1β, Toll-like receptors and the inflammasome are emerging. Targeting IL-12, IL-18, the IL-23/IL-17 system, macrophage migration inhibitory factor and chemokines might be considered. The inhibition of apoptosis of glandular cells, the promotion of cell regeneration and organ-specific stem cell transplantation are potential strategies directed at preserving and restoring functional exocrine tissue. The recognition of patients who benefit most from a particular strategy might help to design more efficient therapeutic approaches. Since efficacy of many agents depends on the presence of residual functional glandular tissue, future studies should focus on patients with recent onset of pSS.