Increased oxidative stress is associated with neuronal cell death during the pathogenesis of multiple chronic neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. Transcriptional activation of protective genes is mediated by a cis-acting element called the antioxidant responsive element (ARE) that binds the transcription factor Nrf2 (NF-E2-related factor 2). Activation of this pathway protects cells from oxidative stress-induced cell death. We hypothesize that Nrf2-ARE activation is a novel neuroprotective pathway that confers resistance to a variety of oxidative stress-related neurodegenerative insults. We have ongoing studies using mouse models of Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), nerve degeneration/regeneration, and amyotrophic lateral sclerosis (ALS). In recent studies, primary neuronal cultures treated with chemical activators of the Nrf2-ARE pathway displayed significantly greater resistance to oxidative stress induced neurotoxicity. Similar cultures generated from ARE-hPAP (human placental alkaline phosphatase) reporter mice demonstrated selective activation of the Nrf2-ARE pathway in astrocytes suggesting that Nrf2 activation in the astrocyte somehow confers resistance to naïve neurons. Furthermore, in chemical models of neurodegeneration, Nrf2 knockout mice are significantly more sensitive to mitochondrial complex I and II inhibitors. Combining these observations with the results implying that the astrocyte is central to Nrf2-ARE mediated neuroprotection, we generated transgenic mice that selectively overexpress Nrf2 in astrocytes using the GFAP (glial fibrillary acid protein) promoter to drive Nrf2 expression. This presentation will discuss how the GFAP-Nrf2 mice affect acute and chronic models of neurodegeneration as well as current research efforts to identify novel natural product activators of Nrf2 isolated from marine invertebrates.