TGF-β1 is a key regulator of diverse biological processes in many tissues and cell types, but its exact function in the developing and adult mammalian CNS is still unknown. We report that lack of TGF-β1 expression in neonatal Tgfb1^−/− mice results in a widespread increase in degenerating neurons accompanied by reduced expression of synaptophysin and laminin and a prominent microgliosis. Lack of TGF-β1 also strongly reduces survival of primary neurons cultured from Tgfb1^−/− mice. TGF-β1 deficiency in adult Tgfb1^−/+ mice results in increased neuronal susceptibility to excitotoxic injury, whereas astroglial overexpression of TGF-β1 protects adult mice against neurodegeneration in acute, excitotoxic and chronic injury paradigms. This study reveals a nonredundant function for TGF-β1 in maintaining neuronal integrity and survival of CNS neurons and in regulating microglial activation. Because individual TGF-β1 expression levels in the brain vary considerably between humans, this finding could have important implications for susceptibility to neurodegeneration.