Muller cells are the predominant glial cell type in the retina and have a unique anatomy, with processes that span the entire retinal thickness. Although extensive morphological and physiological studies of Muller glia have been performed, much less is known about their role in retinal innate immunity, specifically in infectious endophthalmitis. They were found to express toll-like receptors (TLRs), a major family of pattern recognition receptors that mediate innate responses and provide an important mechanism by which Muller glia are able to sense both pathogen- and host-derived ligands in the vitreous and the retina. An increasing body of evidence suggests that TLR-signaling mediates beneficial effects in the retina via production of proinflammatory cytokines/chemokines, antimicrobial peptides, and neuroprotective growth factors to restore tissue homeostasis. In this review, we discussed retinal innate immunity in general with emphasis on the role of Muller glia in initiating retinal innate defense.