The management of patients suffering from primary Sjögren syndrome (pSS) has long been mainly symptomatic and demonstration of effectiveness of systemic drugs was lacking. However, progress made in the understanding of pSS pathogenesis has allowed moving into a more targeted approach to therapeutic intervention. Given the key role of chronic B-cell activation, B-cell target therapies were the first candidates. New pathways are currently being investigated, including costimulation and ectopic germinal center. In this review, we summarize the current evidence regarding B-cell targeted and anti-TNF therapies and provide an overview of promising drugs in the pipeline.