Astrocytes perform vital maintenance, functional enhancement, and protective roles for their associated neurons; however these same mechanisms may become deleterious for neurons under some conditions. In this review, we highlight two normally protective pathways, the endoplasmic reticulum (ER) stress response and an endogenous antioxidant response, which may become neurotoxic when activated in astrocytes during the inflammation associated with neurodegeneration. Stimulation of these multifaceted pathways affects a panoply of cellular processes. Of particular importance is the effect these pathways have on the homeostasis of the excitatory amino acid neurotransmitter, glutamate. The endogenous antioxidant response increases extracellular glutamate in the pursuit of making the cellular antioxidant, glutathione, by increasing expression of the xCT subunit of the cystine/glutamate antiporter. Meanwhile, inflammatory mediators such as TNFα reduce levels of membrane-bound glutamate scavenging proteins such as the excitatory amino acid transporters. Together, these cellular activities may result in a net increase in extracellular glutamate that could alter neuronal function and lead to excitotoxicity. Here we discuss the role of N-methyl-D-aspartate receptors, which, when excessively stimulated by glutamate, can cause neuronal dysfunction and loss via activation of calpains. While there are other pathways acting in concert or parallel to those we describe here, this review explores a rationale to explain how two protective mechanisms may result in neuronal loss during neurodegeneration.