Sjögren Syndrome (SS) is a systemic autoimmune disease with a wide clinical spectrum that extends from sicca symptoms of the mucosal surfaces to extra-glandular systemic manifestations. Understanding of the pathophysiology of primary SS has advanced over recent years, and this, in turn, has presented new targeted treatment options. We provide a brief, up-to-date description of the pathophysiology of SS and the main etiopathogenic pathways implicated in the disease process and review clinical evidence in support of new treatment options targeting these pathways, highlighting successes and failures, and concluding with a summary of gaps in knowledge and where future research should be focused. Direct and indirect B-cell targeted therapies are currently the most promising biological agents in primary SS, especially for systemic involvement, but other pathways (T-cell co-stimulation, cytokine-based therapies, intracellular pathways and gene therapies) are under development. The next 10 years may witness a disruptive therapeutic scenario in primary SS.