Galectin-3 (Gal-3) is a protein expressed by glia that belongs to an ancient family. Gal-3 recognises molecular patterns on pathogens due to the high degree of its binding specificity with carbohydrate recognition domains. Thus, in sponges as well as other invertebrates, galectins are an important component of the primitive innate immune system. Whereas Gal-3's function in driving mammalian inflammation is well known, its function in warding off bacterial and viral infections is not well appreciated. One route of brain infection is via the cerebrospinal fluid brain interface (CSFBI) which is primarily composed of ependymal cells (EC). ECs express high levels of Gal-3, and their motile cilia are compromised in Gal-3 KOs. In this mini-review, we discuss fundamentally important potential roles of Gal-3 in pathogen recognition at the CSFBI and suggest avenues of further study.