Salivary gland gene therapy presents an opportunity to reprogram the organ on the molecular level and achieve unprecedented therapeutic advancements. This chapter will review the basic biology of gene transfer, with emphasis on those vector systems that have performed well in the salivary gland in animal models. Various therapeutic applications of salivary gland gene therapy will be discussed, including radiation-induced xerostomia and Sjögren’s syndrome. The concept of salivary glands as endogenous bioreactors for systemic gene therapeutics in monogenetic and acquired diseases will also be reviewed. A brief history of the field, with regard to animal models, clinical translational studies, and ultimately a successful phase I/II clinical trial, will be presented. The merits and limitations of the several animal models of salivary gland gene therapy will be reviewed. This chapter concludes with a discussion of human salivary gland gene therapy clinical trials, completed and ongoing, and will point out congruence and discord between preclinical animal studies and clinical trials. Salivary gland gene therapy is now established as safe and therapeutically effective in humans, and the near future of this field will be focused on making this technology practical for outpatient use and broadly disseminating it into the practice of oral and dental medicine.