Sjögren’s syndrome (SS) is a complex autoimmune disorder characterized by mononuclear infiltration of the exocrine glands. There is an increased interest to use immunomodulatory protein therapy to target inflammatory components thought to be important in SS. However, systemic immunomodulatory treatment has several limitations and unwanted side effects. One alternative approach is developing localized expression via gene therapy in the salivary glands. Genes encoding cytokines or cDNAs encoding soluble forms of a key cytokine receptor can be introduced directly into the salivary glands, and are likely to alter immune responses locally, but not systemically. While the etiology of SS is unclear, several gene targets are being examined in preclinical studies. The focus of this review is to summarize the approach to developing therapeutic molecules for salivary gland gene transfer that may impact the treatment of SS.