Abstract: Dry eye disease is the most prevalent ocular surface disease in eye clinics. The deficiency of tears is regarded as one of the main pathogenic factors for this disease. Due to the fact that the components of tears are still far beyond our knowledge, the restoration of physiological tears remains the optimum choice for dry eye patients. However, the traditional way to stimulate tear production by systemic administration of muscarinic agonists usually encounters severe side effects. Recently, Nakamachi and colleagues reported that PACAP, a native neurotransmitter present in tear fluid, could stimulate main lacrimal gland secretion and relieve dry eye-like symptoms in PACAP knockout mice. The finding of PACAP and its underlying mechanisms suggest a new modality for dry eye treatment via targeted topical tear stimulations.