Astrocytes perform critical homeostatic support functions in the central nervous system. It is now clear that astrocytes, similar to neurons, can molecularly, morphologically and functionally specialize to brain areas, circuits and other anatomical domains. We have recently discovered that astrocytes forming brain borders in the brain and spinal cord, called glia limitans astrocytes, are highly specialized. These astrocytes have a highly unusual morphology, a unique gene expression profile and are conserved from fish to mouse to human. Our lab now studies the development, function and dysfunction of these cells using -omics, imaging and transgenic approaches to discover their role in protecting the brain from peripheral insults, injury and neuroinflammation.