Primary Sjögren’s Syndrome (pSS) is characterized by focal lymphocytic infiltration of secretory exocrine glands associated with severe dryness of eyes and mouth in particular. Systemic features such as disabling fatigue, cutaneous vasculitis, lung, neurological, haematological or other systemic involvement also occur. Conventional immunosuppressive therapies such as corticosteroids or disease-modifying drugs, have been used in some patients with these systemic features with variable benefit. Current therapy for dryness is principally symptomatic although medications to stimulate residual glandular secretion can be helpful for appropriate individuals. As the pathogenesis of the condition becomes better understood, particularly, in recent years, the role of systemic B-cell activation, biologic therapies specifically targeted against molecules involved in disease pathogenesis represent a more targeted approach to therapeutic intervention. The greatest experience in pSS is with rituximab, an anti-CD20 (expressed on a subset of B-cells) monoclonal antibody already in use for the treatment of some B-cell lymphomas and rheumatoid arthritis. Randomised placebo-controlled studies in pSS are currently underway. This review discusses the rationale for using biologic therapies in pSS, the current data on rituximab and the potential use of other biologic therapies in pSS in the future.