Sjögren’s Syndrome (SS) is a debilitating autoimmune disease that primarily affects women. Patients with SS experience dry eyes and dry mouth in addition to systemic disease manifestations, including arthritis, peripheral neuropathy and pulmonary fibrosis. As in many autoimmune diseases, the inciting factors that precipitate SS are poorly understood. Patients with SS have periductal and perivascular lymphocytic infiltration of salivary and lacrimal tissue, and this is a hallmark of disease. While this infiltration is well characterized, the pathologic events that precede and cause this inflammatory cell recruitment are unknown. Although few studies have examined SS salivary tissue prior to disease onset, there is strong evidence for innate immune hyperactivity. Accordingly, processes such as apoptosis of glandular tissue, heightened inflammatory cytokine and chemokine production, and toll-like receptor (TLR) activation are described in early disease and are each linked to innate immune activation in murine models of disease and SS patients. This review will explore the relationship between innate immunity and SS pathogenesis prior to overt disease onset and discuss therapeutic strategies to mitigate disease progression in SS patients.