Primary Sjögren’s syndrome is a chronic autoimmune disease characterized by salivary and lacrimal gland dysfunction, leading to substantial morbidity and reduced quality of life. Many patients with primary Sjögren’s syndrome also have extraglandular systemic complications, some of which can be organ-or life-threatening. Over the last decade, numerous targeted immunomodulatory therapies for primary Sjögren’s syndrome have failed to show a benefit in clinical trials, and as yet no disease-modifying therapy has been approved for this disease. Herein, we provide an updated review of the clinical trial landscape for primary Sjögren’s syndrome and the numerous efforts to move the field forward, including the development of new classification criteria and outcome measures, the results of recent clinical trials in this field, the challenges faced in the search for effective therapies, and the expanding pipeline of novel therapies under development.