Glycoprotein 340 (Gp340) is an innate immune receptor with well-defined roles in mucosal tissues. It is a normal component of mucosal fluids such as tears, breast milk, and saliva, and it is expressed in tissues such as the vagina, gastrointestinal tract, oral cavity, lung alveoli, and pancreas. In the eye, it is expressed in the lacrimal gland, cornea, conjunctiva, and retina. Investigations of the protein in wet-surfaced epithelia of the body show that the effects of Gp340 can be beneficial or harmful depending on the conformation in which it exists. In a fluid phase, Gp340 appears to be protective against mucosal infection, while in a surface-associated form it appears to promote infection. On the ocular surface, it is dysregulated in dry eye disease and inhibits twitching motility of P. aeruginosa in tears. This review discusses what is known about Gp340 in wet-surfaced mucosal epithelia and highlights the potential roles of the protein in ocular surface immunity, inflammation, and infections.