Innate immunity is a constitutive component of the central nervous system (CNS) and relies strongly on resident myeloid cells, the microglia. However, evidence is emerging that the most abundant glial cell population of the CNS, the astrocyte, participates in the local innate immune response triggered by a variety of insults. Astrocytes display an array of receptors involved in innate immunity, including Toll-like receptors, nucleotide-binding oligomerization domains, double-stranded RNA-dependent protein kinase, scavenger receptors, mannose receptor and components of the complement system. Following activation, astrocytes are endowed with the ability to secrete soluble mediators, such as CXCL10, CCL2, interleukin-6 and BAFF, which have an impact on both innate and adaptive immune responses. The role of astrocytes in inflammation and tissue repair is elaborated by recent in vivo studies employing cell-type specific gene targeting.