Ependymins are fish-specific glycoproteins that play key roles in CNS plasticity and memory formation. Almost a decade ago it was revealed that these ependymins evolved from a related group of proteins comprising both vertebrate and invertebrate members, however the function of these ependymin-related proteins (Epdrs) remains unknown. We have systematically identified Epdrs from both whole genomes and transcriptomes to build a broad picture of the distribution of these genes across Metazoa. We find that the genes encoding these proteins are commonly lost, and have not identified any members in the ecdysozoan species examined to date. We also find that this gene family has undergone significant expansions in other taxa, including the cephalochordate amphioxus, the brachiopod Lingula, the molluscs Crassostrea, Lottia, Pinctada and Haliotis, the echinoderm, Acanthaster planci, the placozoan Trichoplax and the sponge Amphimedon. We investigate the functions of these expanded Epdr complements in different species and find that they play diverse, lineage-specific roles, such as shell patterning in Haliotis, and alarm response in Acanthaster. Along with the originally described role of ependymin proteins in the CNS, the broad range of functions reported here reveals that this family of proteins is particularly amenable to co-option into novel roles.