The expression of phase-II detoxification and antioxidant enzymes is governed by a cis-acting regulatory element named the antioxidant response element (ARE). ARE-containing genes are regulated by the nuclear factor erythroid-2-related factor 2 (Nrf2), a member of the Cap'n'Collar basic-leucine-zipper family of transcription factors. ARE-regulated genes are preferentially activated in astrocytes, which consequently have more efficient detoxification and antioxidant defences than neurons. Astrocytes closely interact with neurons to provide structural, metabolic and trophic support, as well as actively participating in the modulation of neuronal excitability and neurotransmission. Therefore, functional alterations in astrocytes can shape the interaction with surrounding cells, such as neurons and microglia. Activation of Nrf2 in astrocytes protects neurons from a wide array of insults in different in vitro and in vivo paradigms, confirming the role of astrocytes in determining the vulnerability of neurons to noxious stimuli. Here, we review the current data supporting Nrf2 activation in astrocytes as a viable therapeutic approach, not only in acute neuronal damage, but also in chronic neurodegeneration related to oxidative stress.